研究者基本情報

• 博士（薬学）, 北海道大学

• https://researchmap.jp/kmasaki

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201201084846197306
• http://kaken.nii.ac.jp/d/r/70431319.ja.html

• 201201084846197306

• 精神神経科薬剤
• 周産期
• 輸送担体
• 薬物由来副作用
• 薬物相互作用
• 臨床研究
• モノカルボン酸トランスポータ (MCT)

• ライフサイエンス, 医療薬学

• 学士課程, 薬学部
• 修士課程, 生命科学院
• 博士課程, 生命科学院

研究活動情報

• 2026年07月, 第18回日本がん薬剤学会 (JSOPP) 学術大会 最優秀演題賞
  シスプラチン起因性腎障害に対するセレコキシブの影響：ロキソプロフェン・ナプロキセンとの後方視比較検証
  岡本敬介;齋藤佳敬;高橋健太;武隈洋;榊原純;鳴海克哉;上田一奈太;菅原満;小林正紀
• 2026年07月, 第9回フレッシャーズ・カンファランス 優秀演題発表賞
  MCF10F 乳腺上皮モデルを用いたADHD治療薬 atomoxetine の乳汁移行性と寄与因子の検討
  青栁亮一;古堅彩子;鳴海克哉;岡本敬介;上田一奈太;小林正紀
• 2026年05月, 日本薬学会北海道支部第153回例会 学生優秀発表賞（口頭発表）
  第三世代抗てんかん薬の胎盤移行性に関する研究
  植田彩文, 古堅彩子, 西村あや子, 馬詰武, 青栁亮一, 岡本敬介, 鳴海克哉, 上田一奈太, 小林正紀
• 2026年05月, Author Service Award 2026 for your contributions to Journal of Pharmaceutical Health Care and Sciences
  Masaki Kobayashi
• 2026年04月, 日本薬学会第146年会学生優秀発表賞（口頭発表の部）
  ADHD治療薬のヒト乳汁移行性の解明：ヒト乳汁中薬物濃度解析と乳腺モデル細胞による評価
  青栁亮一 , 古堅彩子, 西村あや子, 馬詰武, 石川修平, 鳴海克哉, 岡本敬介, 上田一奈太, 小林正紀
• 2026年02月, 令和7年度旭川薬剤師会・旭川病院薬剤師会合同フォーラム 優秀演題賞
  CS分析（Customer Satisfaction analysis）を応用した薬剤業務補助者への研修・教育に対する満足度調査
  菊谷 由里香;寺田 和文;森 綾子;鳴海 克哉;上田 一奈太;岡本 敬介;廣川 力教;小林 正紀
• 2025年11月, 第35回日本医療薬学会年会 優秀演題賞
  基礎・臨床研究によるセレコキシブがシスプラチン起因性腎障害に及ぼす影響の検証
  岡本 敬介、齋藤 佳敬、高橋 健太、武隈 洋、榊原 純、鳴海 克哉、上田 一奈太、菅原 満、小林 正紀
• 2025年11月, 第19回日本薬局学会学術総会 優秀演題賞
  胃酸分泌抑制薬がカペシタビンによる手足症候群に及ぼす影響の検証―薬局の電子薬歴データを用いた解析―
  岡本 敬介、鈴木 直哉、谷口 亮央、染谷 光洋、石川 修平、穴田 わかな、上田 一奈太、鳴海 克哉、小林 正紀
• 2025年06月, 日本医療薬学会 第8回 フレッシャーズ・カンファランス 優秀演題
  モノカルボン酸輸送担体の発現とがんの予後に関するメタ解析及びin vitroにおける検討
  向井 悠斗、 山口 敦史、 菅沼 雄大、 岡本 敬介、 松本 憲之、 上田 一奈太、 鳴海 克哉、 小林 正紀
• 2025年05月, Author Service Award 2025 for your contributions to Journal of Pharmaceutical Health Care and Sciences
  Masaki Kobayashi
• 2025年05月, 日本薬学会北海道支部第152回例会 学生優秀発表賞 （ポスター発表）
  モノカルボン酸輸送担体MCTsの阻害が肝がん細胞株の生存及びエネルギー代謝に与える影響
  松本 憲之、向井 悠斗、菅沼 雄大、村松 ゆかり、山口 敦史、上田 一奈太、岡本 敬介、鳴海 克哉、山田 勇磨、小林 正紀
• 2024年10月, 第18回次世代を担う若手医療薬科学シンポジウム 優秀発表賞
  アルデヒドオキシダーゼの薬物動態学的重要性および個体間差の解明
  上田 一奈太、鳴海 克哉、岡本 敬介、古堅 彩子、小林 正紀
• 2024年08月, 第37回 北海道薬物作用談話会 若手研究者優秀発表賞（口頭発表）
  糖尿病治療薬がシスプラチン起因性腎障害に及ぼす影響の評価
  坂田 浩太郎、岡本 敬介、齋藤 佳敬、古堅 彩子、鳴海 克哉、小林 正紀
• 2024年07月, 第40回日本TDM学会・学術大会 学生優秀演題賞 （口頭発表）
  オレキシン受容体拮抗薬のUPLC/MS/MS定量法構築とヒト乳汁移行性評価への応用
  石川 陽菜、古堅 彩子、西村 あや子、馬詰 武、青栁 亮一、石川 修平、鳴海 克哉、岡本 敬介、武隈 洋、菅原 満、小林 正紀
• 2024年07月, 日本薬学会北海道支部第151回例会 学生優秀発表賞 （口頭発表）
  ヒト胎盤幹細胞におけるトランスポーター発現・機能評価
  澤田 理子、古堅 彩子、植田 彩文、西村 あや子、馬詰 武、鳴海 克哉、岡本 敬介、小林 正紀
• 2023年07月, 医療薬学ﾌｫｰﾗﾑ2023／第31回ｸﾘﾆｶﾙﾌｧｰﾏｼｰｼﾝﾎﾟｼﾞｳﾑ優秀ポスター賞
  メトトレキサート誘発性肝障害におけるアルデヒドオキシダーゼの寄与 ―基礎および薬剤疫学的アプローチによる検証―
  鳴海 克哉、森山 綾子、上田 一奈太、淺野 秀峰、古堅 彩子、小林 正紀
• 2023年03月, 日本薬学会 第143年会 優秀発表賞
  アザチオプリン誘発性血液障害および肝障害発現における Aldehyde oxidase 阻害薬剤の影響
  上田 一奈太、鳴海 克哉、古堅 彩子、小林正紀
• 2022年08月, 第35回北海道薬物作用談話会 若手研究者優秀発表賞
  メトトレキサート誘発性肝障害におけるaldehyde oxidase 1の関与
  森山 綾子、鳴海 克哉、上田 一奈太、古堅 彩子、小林 正紀
• 2022年06月, 日本医療薬学会 第5回 フレッシャーズ・カンファランス 優秀演題
  AOX1遺伝子のT755I多型は二量体形成および代謝活性を低下させる
  上田 一奈太、鳴海 克哉、古堅 彩子、小林 正紀
• 2022年05月, 日本薬学会北海道支部第149回例会学生優秀発表賞 （口頭発表部門）
  肝がん由来細胞において乳酸輸送に寄与する輸送担体の同定に関する研究
  向井 悠斗、山口 敦史、佐久間 智也、古堅 彩子、鳴海 克哉、小林正紀
• 2021年03月, 日本薬学会 第141年会 優秀発表賞
  シスプラチンの副作用と耐性化に着目したNSAIDsの効果の検証
  岡本 敬介、齋藤 佳敬、上田 一奈太、古堅 彩子、鳴海 克哉、小林 正紀
• 2020年11月, 第14回次世代を担う若手医療薬科学シンポジウム 優秀発表賞
  クロザピン誘発性流涎症のリスク因子の同定と発現メカニズムの解明
  石川 修平、小林 正紀、橋本 直樹、久住 一郎
• 2017年01月, 北海道大学, 教育総長賞 (奨励賞)
  小林 正紀
• 2015年11月, 第２５回日本医療薬学会奨励賞
  MCTの役割に着目した疾患と副作用に関する研究
  小林 正紀
• 2014年05月, 日本薬学会北海道支部 奨励賞
  脂質異常症治療薬の副作用・薬物相互作用におけるモノカルボン酸トランスポータの役割
  小林 正紀

• Everolimus Breast Milk Transfer After Liver Transplantation
  Nozomi Yoshimoto; Hinata Ueda; Masaki Kobayashi; Katsuya Narumi; Keisuke Okamoto; Satoshi Matsuzawa; Kayo Tomimori; Michika Yamaguchi; Naoki Yoshikawa; Ryuji Ikeda; Shinji Katsuragi
  BREASTFEEDING MEDICINE, 2026年08月23日
  英語, 研究論文（学術雑誌）
• Modulation of remimazolam placental transfer via OATP2B1 by rosuvastatin in an in vitro 3D placental barrier model
  Satoshi Sato; Tomohiro Chaki; Katsuya Narumi; Tomoki Hirahata; Tsuyoshi Aoyama; Masaki Kobayashi; Takaki Toda; Michiaki Yamakage
  European Journal of Pharmaceutical Sciences, 223, 107565, 107565, Elsevier BV, 2026年08月, ［査読有り］
  研究論文（学術雑誌）
• Automating the roter interaction analysis system for medication counseling: A transformer-based deep learning approach with generative AI-augmented data.
  Ayako Mori; Satoshi Watabe; Izumi Kato; Katsuya Narumi; Yoh Takekuma; Hayato Kizaki; Shungo Imai; Keisuke Okamoto; Hinata Ueda; Mitsuru Sugawara; Satoko Hori; Masaki Kobayashi
  Research in social & administrative pharmacy : RSAP, 2026年06月17日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: The Roter Interaction Analysis System (RIAS) is the gold standard for medical communication analysis, but its automated coding remains underexplored due to imbalanced code distributions. This study developed an automated RIAS classification system using Japanese transformer-based models and evaluated AI-based data augmentation to mitigate class imbalance. METHODS: Five transformer models were fine-tuned for 44-class RIAS classification using medication counseling dialogues. To enhance generalizability, we employed AI-based data augmentation and evaluated performance using both AI-augmented and real-data-only test sets. Assessment metrics included accuracy, macro F1, and weighted F1. FINDINGS: The dataset comprised 17,391 utterances (39.4% AI-generated). In the real-data-only (primary) test set, ELECTRA achieved the highest accuracy (0.7875), macro F1 (0.6561), and weighted F1 (0.7835). All models performed worse under the real-data-only condition than under the AI-augmented condition, mainly for minority-class categories. Error analysis showed semantically ambiguous and context-dependent categories, including domain-adjacent counseling topics and affective expressions, remained challenging, indicating linguistic transparency and definitional distinctiveness influence classification beyond training frequency. CONCLUSION: This proof of concept shows that AI-based augmentation can mitigate class imbalance in automated RIAS classification of medication counseling dialogues. While robust for prototypical expressions, nuanced affective categories remain challenging for text-only approaches. These findings support the feasibility of automated RIAS analysis for pharmacy education while suggesting that multimodal approaches are needed to capture subtle emotional dynamics. By complementing manual coding with quantitative insights, this system may support timelier and objective feedback and ultimately contribute to patient-centered care.
• UPLC–MS/MS Method for Quantifying Non-stimulant ADHD Medications in Human Breast Milk and Plasma: Application in a Lactating Patient Receiving Atomoxetine
  Ryoichi Aoyagi; Ayako Furugen; Ayako Nishimura; Takeshi Umazume; Shuhei Ishikawa; Katsuya Narumi; Keisuke Okamoto; Hinata Ueda; Masaki Kobayashi
  Journal of Pharmaceutical and Biomedical Analysis, 117575, 117575, Elsevier BV, 2026年05月, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Evaluation of intestinal absorption of deoxyribonucleic acid components in salmon milt extract using in-situ and in-vitro gastrointestinal absorption models.
  Rin Taguchi; Katsuya Narumi; Hinata Ueda; Hiroshi Satoh; Takao Mori; Keisuke Okamoto; Ayako Furugen; Masaki Kobayashi
  Bioscience, biotechnology, and biochemistry, 90, 4, 554, 560, 2026年03月20日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Salmon milt extract (SME) is rich in deoxyribonucleic acids and has been suggested as a functional material. However, whether these components contribute to SME's functionality remains unclear, and data on their intestinal absorption are limited. This study investigated absorption mechanisms of deoxyribonucleic acid components in SME using in-situ and in-vitro models. Ultra-performance liquid chromatography/tandem mass spectrometry was used to simultaneously quantify four deoxyribonucleosides (dNs). The in-situ rat intestinal loop study showed increased levels of 2'-deoxyadenosine (dAdo) and 2'-deoxyguanosine (dGuo) in the portal vein. In the transcellular transport assay, dAdo and dGuo levels on the receiver side increased in a time-dependent manner after SME treatment, particularly in human induced pluripotent stem cell-derived small intestinal epithelial cells. No increase in 2'-deoxycytidine or thymidine levels was observed under any experimental condition. These results indicate that purine dNs are absorbed into the portal vein after oral intake of SME, whereas intestinal absorption of pyrimidine dNs is limited.
• Placental transfer of third-generation antiepileptic drugs: in vivo lacosamide case study and in vitro investigation of transporter inhibition by lacosamide and perampanel
  Ayami Ueda; Ayako Furugen; Ayako Nishimura; Takeshi Umazume; Ryoichi Aoyagi; Keisuke Okamoto; Katsuya Narumi; Hinata Ueda; Masaki Kobayashi
  Journal of Pharmaceutical Health Care and Sciences, 12, 1, Springer Science and Business Media LLC, 2026年01月24日, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Ganoderic Acid A Derived from Reishi Mushroom Ganoderma lucidum Protects against Intestinal Immunity Reduction Due to Oxidative Stress in Rat.
  Atsuhito Kubota; Keisuke Okamoto; Genki Yasuda; Katsuya Narumi; Yuji Suzuki; Hinata Ueda; Ayako Mori; Natsuko Takahashi-Suzuki; Takashi Satoh; Ken Iseki; Masaki Kobayashi
  Biological & pharmaceutical bulletin, 49, 4, 701, 707, 2026年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, Reishi (Ganoderma lucidum) is known to enhance intestinal immunity, with ganoderic acid A (GA-A) identified as one of its active constituents. However, the specific role of GA-A in regulating immune components such as immunoglobulin A (IgA) from Peyer's patches (PPs) and α-defensin 5 from Paneth cells remains unclear. Additionally, the ability of Reishi to counteract oxidative stress-induced intestinal immune suppression has not been fully elucidated. Therefore, in this study, we aimed to examine the effects of Reishi and GA-A on intestinal immunity in a rat model of ischemia-reperfusion (I/R) injury. Oral administration of GA-A increased IgA secretion from PP cells isolated from rat small intestine and upregulated the mRNA expression of rat α-defensin 5 (RD-5) and toll-like receptor 4 (TLR4) in the ileum, similar to Reishi. In contrast, GA-A did not exhibit immunostimulatory effects in TLR4-deficient mice. In the I/R rat model, both Reishi and GA-A significantly restored IgA secretion and RD-5 mRNA expression, mitigating immune suppression. They were also associated with changes in superoxide dismutase 1 (SOD1) and SOD3 mRNA expression under I/R conditions and prevented villus shedding and Paneth cell loss, indicating protection against I/R-induced intestinal immune decline. These results were comparable to those observed with caffeic acid, the positive control. Overall, these findings suggest that Reishi mitigates intestinal immune suppression caused by I/R injury, with GA-A serving as a key active component mediating these protective effects.
• Quetiapine competitively inhibits aldehyde oxidase-mediated reduction.
  Hinata Ueda; Shuho Asano; Katsuya Narumi; Ryoichi Aoyagi; Keisuke Okamoto; Masaki Kobayashi
  Drug metabolism and disposition: the biological fate of chemicals, 53, 11, 100169, 100169, 2025年09月24日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Aldehyde oxidase (AOX) oxidizes nitrogen-containing heterocyclic drugs and reduces electron-deficient nitroaromatic drugs. The aim of this study was to elucidate the mode of inhibition of benzothiazepines such as quetiapine and clozapine, which are known inhibitors of AOX, to predict drug-drug interactions between AOX substrates and inhibitors. Quetiapine and its metabolites inhibited the oxidation and reduction activities of AOX (inhibitory effects: quetiapine ≈ norquetiapine > quetiapine sulfoxide > quetiapine carboxylic acid). The inhibition mode of quetiapine was noncompetitive for phthalazine oxidation (Ki, 5.72 ± 0.88 μM) and competitive for flunitrazepam reduction (Ki, 5.71 ± 0.34 μM). Although a mixed inhibition mode was indicated for the reduction of AOX by clozapine (Ki, 30.91 ± 4.02 μM), the affinity for the enzyme-substrate complex was estimated to be lower than its affinity for the substrate-free enzyme. On the basis of these results, we expected that benzothiazepines would inhibit activity by becoming trapped in the pocket of AOX, where the electron donor resides. Quetiapine and its metabolites did not inhibit xanthine oxidase activity, and it is assumed that there are significant structural differences in the sites where the reduction reactions of AOX and xanthine oxidase occur. To our knowledge, this is the first study to identify drugs that competitively inhibit the AOX-mediated reduction reactions. The affinities of the inhibitors, especially quetiapine, were higher than those of flunitrazepam used in this study. When evaluating the combined effects of competitive inhibitors on substrate drugs, attention should be paid to the concentrations of both the substrate and the inhibitor. SIGNIFICANCE STATEMENT: Quetiapine inhibited the oxidative reaction of aldehyde oxidase noncompetitively and the reductive reaction competitively, suggesting that benzothiazepines tend to bind to the reductive pocket of aldehyde oxidase.
• Effect of Acid Suppressants on Adverse Events of Immune Checkpoint Inhibitors Using Real-world Databases.
  Keisuke Okamoto; Juri Takizawa; Hinata Ueda; Katsuya Narumi; Masaki Kobayashi
  Anticancer research, 45, 8, 3287, 3293, 2025年08月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) in various organs. Although many studies have suggested that acid suppressants (ASs) may affect irAEs, limited sample sizes have hindered detailed evaluations. Therefore, this study aimed to assess the impact of ASs on individual irAEs using large real-world databases, the Japanese Adverse Drug Event Report database (JADER) and the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). MATERIALS AND METHODS: We analyzed adverse event (AE) reports from the JADER and FAERS databases to assess the impact of ASs on ICI-related AEs. Reporting odds ratios (RORs) and 95% confidence intervals (95%CI) were calculated. Drug-drug interaction signals were defined by non-overlapping 95%CIs between ICIs alone and their combination use. RESULTS: Co-administration with ASs or proton pump inhibitors (PPIs) was associated with an increased risk of acute kidney injury (AKI) in both datasets, while H2-receptor antagonists (H2RAs) showed weaker or no signals. The incidence of endocrine-related AEs tended to decrease with ASs. The colitis results differed between the two datasets, with a decreased incidence in the JADER and an increased incidence in FAERS. Other ICI-related AEs showed consistent trends across datasets. Subgroup analyses of individual PPIs revealed varying results for AKI and colitis between the JADER and FAERS databases, with no consistent trends across PPIs. CONCLUSION: ASs have diverse effects on ICI-induced AEs and their characteristics may differ between PPIs and H2RAs.
• Celecoxib has less aggravating effect on cisplatin-induced nephrotoxicity in comparison with non-selective cyclooxygenase inhibitors: a retrospective multi-institutional study.
  Keisuke Okamoto; Yoshitaka Saito; Kenta Takahashi; Yoh Takekuma; Jun Sakakibara-Konishi; Katsuya Narumi; Mitsuru Sugawara; Masaki Kobayashi
  International journal of clinical oncology, 2025年07月07日, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Cisplatin (CDDP)-induced nephrotoxicity (CIN) is one of its most serious adverse effects. Although we previously demonstrated that celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, attenuates CIN in a basic study, there are no reports that have evaluated its clinical impact on CIN. Therefore, we aimed to determine the effect of celecoxib on CIN compared with that of non-selective COX inhibitors. METHODS: Patients with lung cancer receiving CDDP (≥ 60 mg/m2)-containing regimens with regular administration of loxoprofen or naproxen (COX-1 group), or celecoxib were evaluated in this retrospective, multi-institutional study. The primary endpoint was the evaluation of CIN incidence in all treatment cycles between the groups. In addition, the variance in creatinine clearance (CCr) and the incidence of gastrointestinal adverse effects were evaluated. RESULTS: CIN occurred in 24.2% of patients in the COX-1 group (n = 33) and 0% of those in the celecoxib group (n = 15) in all cycles, showing a significant difference (P = 0.04). In addition, the variance in CCr was significantly smaller in the celecoxib group than in the COX-1 group in all cycles, as well as at the primary endpoint (P = 0.02). However, there was no difference in the incidence of CIN or variance in CCr in the first cycle between the two groups. The incidences of nausea, vomiting, and anorexia were similar between the groups, implying a similar amount of oral hydration. CONCLUSION: These findings suggest that celecoxib is less aggravating on CIN than non-selective COX inhibitors.
• Analysis of drug transporter expression in syncytiotrophoblast derived from human placental stem cells: Expression and function of efflux transporters.
  Riko Sawada; Ayako Furugen; Ayami Ueda; Ayako Nishimura; Takeshi Umazume; Katsuya Narumi; Masaki Kobayashi
  Placenta, 165, 23, 32, 2025年03月27日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVE: The placenta is a vital organ for exchanging nutrients, endogenous substances, and xenobiotics between mother and fetus. The syncytiotrophoblast (ST) is crucial in maintaining the placental barrier. Human trophoblast stem cells (hTSCs) have been recently established; however, their utility in studying placental transport functions has not been fully elucidated. This study investigated the expression and function of transporters in hTSC-derived ST cells. METHODS: TSCT cells, as hTSCs, were differentiated into ST-like cells (ST-TSCT), and the gene expression of 84 transporters in ST-TSCT cells was evaluated using a PCR array. BeWo cells, a widely used trophoblast model, were used for comparison. BeWo cells were differentiated into ST-like cells using forskolin [BeWo (FK)]. The protein levels of efflux transporters were examined by western blotting, and functional assays were performed using typical fluorescent substrates. RESULTS: Transporter gene expression levels were higher in ST-TSCT than in BeWo (FK) cells, with 27 genes showing more than a 3-fold increase. Ten of these genes were exclusively expressed in ST-TSCT. Western blotting revealed the presence of efflux transporters, including P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 2 (MRP2/ABCC2). Furthermore, the accumulation of typical substrates (Rhodamine123 for P-gp, Hoechst33342 and BODIPY™ FL Prazosin for BCRP, and 5(6)-carboxy-2',7'-dichlorofluorescein diacetate for MRP) significantly increased when transporter inhibitors (elacridar, Ko143, and MK571) were applied. CONCLUSION: This study showed higher transporter expression in ST-TSCT than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TSCT is valuable for investigating placental transport functions.
• HYA ameliorated postprandial hyperglycemia in type 1 diabetes model rats with bolus insulin treatment.
  Yuta Yamamoto; Katsuya Narumi; Naoko Yamagishi; Yasunori Yonejima; Ken Iseki; Masaki Kobayashi; Yoshimitsu Kanai
  Acta diabetologica, 2025年02月03日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, AIMS: The oral administration of linoleic acid immediately before glucose tolerance test (OGTT) ameliorated postprandial hyperglycemia via GPR120 pathway in normal and type 1 diabetes (T1DM) rats. Linoleic acid could promote inflammatory mediators, but 10-hydroxy-cis-12-octadecenoic acid (HYA) converted from linoleic acid by Lactobacillus plantarum has higher GPR120 agonistic activity without promoting inflammatory mediators. This study examined whether the oral-administration of HYA immediately before OGTT also ameliorated the postprandial hyperglycemia in normal rats and T1DM rats injected with bolus insulin. METHODS: Normal and T1DM male Sprague-Dawley rats received HYA immediately before OGTT. Other T1DM rats were given HYA and Humulin R immediately before OGTT. We measured the concentration of glucose, insulin, glucagon-like peptide 1 (GLP-1) and cholecystokinin in blood before and after OGTT. We also measured the amount of glucose in the gastric tract after OGTT, and the amount of uptake of methyl-α-D-glucopyranoside in CACO-2 cells. RESULTS: Postprandial hyperglycemia was ameliorated by HYA in normal rats, and the postprandial blood glucose levels were slowly elevated by HYA in the T1DM model rats. HYA partially inhibited the uptake of methyl-α-D-glucopyranoside in CACO-2 cells. HYA slowed gastric motility and increased the plasma GLP-1 and cholecystokinin levels in normal rats. HYA also ameliorated the postprandial hyperglycemia in T1DM rats given bolus insulin. CONCLUSION: Oral administration of HYA immediately before OGTT ameliorated postprandial hyperglycemia through inhibition of glucose absorption and slowing of gastric motility in normal rats. Furthermore, this beneficial effect of HYA was also revealed in T1DM rats injected with bolus insulin.
• Validity and Utility of a Risk Prediction Model for Wound Infection After Lower Third Molar Surgery
  Akira Yamagami; Katsuya Narumi; Yoshitaka Saito; Ayako Furugen; Shungo Imai; Keisuke Okamoto; Yoshimasa Kitagawa; Yoichi Ohiro; Ryo Takagi; Yoh Takekuma; Mitsuru Sugawara; Masaki Kobayashi
  Oral Diseases, Wiley, 2025年01月10日, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）, ABSTRACT
  
  Objectives
  
  To externally validate a clinical prediction model for surgical site infection (SSI) after lower third molar (L3M) surgery and evaluate its clinical usefulness.
  
  Methods
  
  We conducted a retrospective cohort study of patients who underwent L3M surgery at Hokkaido University Hospital. The study was designed to evaluate the historical and methodological transportability. Clinical usefulness was evaluated using decision curve analysis on the data of the non‐antibiotic‐treated patients.
  
  Results
  
  We obtained 2543 validation cohorts from April 2020 to March 2023, and 640 non‐antibiotic cohorts from July 2010 to September 2023. The incidences of SSI after L3M surgery were 5.3% (135/2543) and 7.7% (49/640) in the validation and non‐antibiotic cohorts, respectively. The discrimination ability of the prediction model was acceptable for the external validation cohort (c‐statistic: 0.67; 95% CI: 0.62–0.71) and adequate for the non‐antibiotic cohort (c‐statistic: 0.72; 95% CI: 0.63–0.79). In both cohorts, the model showed excellent calibration between the observed and predicted probabilities. Decision curve analysis showed increased net benefit across a range of meaningful risk thresholds.
  
  Conclusion
  
  A simple risk prediction model for SSI after L3M surgery demonstrated clinical transportability and usefulness. This model may help surgeons/clinicians determine the appropriateness of prophylactic antibiotics administration for patients in L3M surgery.
• Association between the Expression of Monocarboxylate Transporters in Tumors and Surrounding Stromal Cells and Cancer Prognosis: A Meta-Analysis.
  Yuto Mukai; Atsushi Yamaguchi; Yudai Suganuma; Keisuke Okamoto; Noriyuki Matsumoto; Katsuya Narumi; Masaki Kobayashi
  Biological & pharmaceutical bulletin, 48, 12, 1960, 1971, 2025年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, l-Lactate is not merely a metabolic product of glycolysis but also a molecule that plays an important role in intercellular interactions. Monocarboxylate transporters (MCTs) 1-4 are membrane proteins responsible for transporting monocarboxylic acids, such as l-lactate, across the plasma membrane. MCTs have been suggested to be involved in cancer cell invasion, metastasis, and immune evasion. Several studies have reported the relationship between MCT expression in tumor tissues and cancer prognosis. However, the potential for MCTs as poor prognostic factors in cancer remains controversial, and the impacts of different MCT isoforms and cancer types are yet to be fully elucidated. Therefore, we conducted a meta-analysis by pooling previously reported hazard ratios. The expression of MCT1 and MCT4, but not MCT2, in tumors and MCT4 in stromal cells was significantly associated with cancer prognosis. In addition, subgroup analyses revealed that both MCT1 and MCT4 expression were associated with esophageal cancer prognosis, whereas MCT4 expression was associated with hepatocellular carcinoma prognosis. Unlike MCT1, the plasma membrane expression of MCT4 was found to be associated with cancer prognosis. Put together, our findings show that MCT4 is a promising target for the treatment of various cancers. Further integration of basic and clinical research is required to elucidate the mechanisms by which MCTs contribute to poor cancer prognosis, in turn facilitating the development of effective inhibitors.
• Evaluation of the Effect of Aldehyde Oxidase Inhibitors on 6-Mercaptopurine Metabolism.
  Hinata Ueda; Katsuya Narumi; Ayako Furugen; Keisuke Okamoto; Yoshitaka Saito; Masaki Kobayashi
  Biological & pharmaceutical bulletin, 48, 5, 713, 720, 2025年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, Thiopurines, such as 6-mercaptopurine (6-MP) and azathioprine, are converted to the inactive metabolites 6-thioxanthin (6-TX) and 6-thiouric acid (6-TUA). Molybdenum-containing oxidoreductases, aldehyde oxidase (AOX) and xanthine oxidase (XO), are involved in the oxidation of 6-MP to 6-TX; XO inhibitors affect the therapeutic efficacy of thiopurines and the incidence of adverse effects, such as liver and blood disorders. However, the role of AOX in the pharmacokinetics of 6-MP remains unclear. To clarify the clinical importance of AOX-mediated drug-drug interactions, we evaluated whether drugs that inhibit AOX affect 6-MP metabolism. The metabolism of 6-MP to 6-TX was strongly inhibited by AOX inhibitors (amitriptyline, chlorpromazine, clomipramine, clozapine, hydralazine, quetiapine, and raloxifene) in a reaction mixture containing human liver cytosol. The inhibition of 6-TX production rate by each AOX inhibitor was 60-70% at high concentrations, although the XO inhibitor febuxostat showed an inhibition rate of 10-30%. Furthermore, the combination of febuxostat and each AOX inhibitor showed greater inhibition than when each compound was added alone. The AOX inhibitor did not alter 6-MP oxidation by recombinant XO. These results suggest that AOX inhibition may affect the pharmacokinetics of thiopurines. However, because of the lower activity of AOX in rats than that in humans, the contribution of AOX could not be assessed using in vivo experiments. Further studies are needed to evaluate the contribution of AOX to the therapeutic and adverse effects of thiopurines, both in clinical studies and in animal models of liver humanization.
• Impact of Eye Contact on Communication during Online Medication Counseling: An Analysis Using the Roter Interaction Analysis System.
  Ayako Mori; Izumi Kato; Katsuya Narumi; Yoh Takekuma; Shuhei Ishikawa; Hitoshi Kashiwagi; Yuki Sato; Mitsuru Sugawara; Masaki Kobayashi
  Biological & pharmaceutical bulletin, 48, 1, 17, 22, 2025年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, We have previously used the Roter Interaction Analysis System (RIAS) to analyze differences between online and face-to-face medication counseling. In our previous research, students have commented that the built-in camera on their laptops makes it difficult to make eye contact and communicate effectively. Furthermore, there is a lack of research on the impact of eye contact in online medical communication. Therefore, this study aimed to investigate the effects of eye contact on online medication counseling. Two simulated patients (SPs) and 10 pharmacy students acting as pharmacists were enrolled in this clinical study (ID:2022-001). Participants were divided into 2 groups: one using cameras designed to naturally align eye contact and another using standard device cameras. The dialogues were segmented into meaningful minimal units (utterances), categorized using RIAS according to their nature, and analyzed. Scenarios with aligned eye contact significantly increased the total number of SP utterances and the occurrence and proportion of "Check" utterances by students, confirming their understanding. The increase in the total utterance count of SPs was associated with a corresponding increase in the number of "Agree" utterances indicating agreement and understanding. Thus, eye contact enhances the clarity of patient responses and proactively confirms patient understanding, thereby mitigating the difficulty of assessing comprehension and conducting bidirectional communication online. This study's findings quantitatively suggested that eye contact in online medication counseling enhances proactive engagement in communication for pharmacy students and SPs.
• Validated UPLC-MS/MS method for quantification of melatonin receptor agonists and dual orexin receptor antagonists in human plasma and breast milk: Application to quantify suvorexant and lemborexant in clinical samples
  Hina Ishikawa; Ayako Furugen; Ayako Nishimura; Takeshi Umazume; Shuhei Ishikawa; Ryoichi Aoyagi; Katsuya Narumi; Keisuke Okamoto; Yoh Takekuma; Mitsuru Sugawara; Masaki Kobayashi
  Journal of Pharmaceutical and Biomedical Analysis, 251, 116432, 116432, Elsevier BV, 2024年12月, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Effects of famotidine use during pregnancy: an observational cohort study.
  Ayako Nishimura; Ayako Furugen; Masaki Kobayashi; Yoh Takekuma; Naho Yakuwa; Mikako Goto; Masahiro Hayashi; Atsuko Murashima; Mitsuru Sugawara
  Journal of pharmaceutical health care and sciences, 10, 1, 70, 70, 2024年11月08日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Famotidine, a histamine2-receptor antagonist (H2Ras), is widely used to treat and prevent gastrointestinal symptoms during pregnancy. Although several studies have reported the use of H2Ras during pregnancy, limited data on famotidine were included in these reports. Therefore, we analyzed pregnancy outcome data to evaluate the effects of famotidine use during pregnancy on the fetus. METHODS: Pregnancy outcome data were used for females enrolled in two Japanese facilities that provided counseling on drug use during pregnancy between April 1988 and December 2017. For the primary endpoint, the incidence of congenital malformations was calculated from the data of live birth to pregnant women who took famotidine (n = 330) or drugs considered to exert no teratogenic risk (control, n = 1,407) during the first trimester of pregnancy. Considering secondary endpoints, the incidence of obstetric outcomes, including preterm delivery, was calculated from data on the use of famotidine (n = 347) and controls (n = 1,476) during the entire pregnancy. The crude odds ratios (cORs) for the incidence of congenital malformations were calculated using univariate logistic regression analysis, with the control group used as the reference. Adjusted ORs (aORs) were calculated using multivariate logistic regression analysis adjusted for various other factors. RESULTS: The incidences of congenital malformations in the famotidine and control groups were 3.9% and 2.8%, respectively. There was no significant difference between the famotidine and control groups (cOR: 1.40 [95% CI:0.68-2.71], aOR: 1.06 [95% CI:0.51-2.16]). Conversely, the preterm delivery rates were 8.1% and 3.8% in the famotidine and control groups, respectively, indicating a significant difference (cOR: 2.00 [95% CI:1.20-3.27]). However, the multivariate analysis eliminated famotidine use as a confounding factor. CONCLUSIONS: This observational cohort study revealed that exposure to famotidine during the first trimester of pregnancy was not associated with an increased risk of congenital malformations in infants. Although a higher rate of preterm delivery was detected in famotidine users when compared with controls, this could be attributed to confounding factors, such as complications.
• Relationship between magnesium dosage and the preventive effect on cisplatin-induced nephrotoxicity: meta-analysis and meta-regression analysis
  Keisuke Okamoto; Yoshitaka Saito; Atsushi Yamaguchi; Katsuya Narumi; Masaki Kobayashi
  International Journal of Clinical Oncology, Springer Science and Business Media LLC, 2024年09月24日, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Salmon Milt Extract Suppresses Glucose Uptake by Downregulating SGLT1 and GLUT2 Expression in Caco-2 Cells
  Taichi Sato; Katsuya Narumi; Rin Taguchi; Komei Ishihara; Hiroshi Satoh; Takao Mori; Keisuke Okamoto; Ayako Furugen; Masaki Kobayashi
  Biological and Pharmaceutical Bulletin, 47, 9, 1477, 1483, Pharmaceutical Society of Japan, 2024年09月04日, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, Salmon milt extract (SME) is rich in nucleotides, especially deoxyribonucleoside monophosphates (dNMPs), which has the potential to exert anti-obesity effects. Sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are responsible for absorbing sugar from the small intestine. The purpose of this study was to examine the effects of SME on the functions of SGLT1 and GLUT2 and elucidate the mechanisms underlying the inhibition of glucose absorption by SME. We investigated the effect of SME on the expression and function of intestinal glucose transporters, using differentiated Caco-2 cells. SME treatment decreased the expression SGLT1 and GLUT2 mRNA and protein in Caco-2 cells. [14C]-Labelled methyl-α-D-glucopyranoside and [3H]-labelled 2-deoxy-D-glucose (DG) uptake into Caco-2 cells was significantly reduced by SME treatment. Similarly, the dNMP mixture containing the four mononucleotides 2'-deoxyadenosine 5'-monophosphate (dAMP), 2'-deoxyguanosine 5'-monophosphate (dGMP), 2'-deoxycytidine 5'-monophosphate (dCMP), and 2'-deoxythymidine 5'-monophosphate (dTMP) decreased SGLT1 and GLUT2 expression. dNMP mixture-induced reduction in the mRNA expression of these transporters was suppressed when exposed to the mixture without dTMP. Furthermore, dNMP mixture-induced alterations in the expression of hepatocyte nuclear factor (HNF)-1α and HNF1β, which have been characterized as modulators of both transporters also showed a similar trend. dTMP treatment alone decreased GLUT2 expression, resulting in reduced [3H] DG uptake by Caco-2 cells. SME decreased the expression of HNF1α, HNF1β, and its targets SGLT1 and GLUT2, resulting in reduced glucose uptake by Caco-2 cells. In addition, our results revealed that dTMP plays an important role in suppressing the expression of intestinal glucose transporters.
• Alteration in folate carrier expression via histone deacetylase inhibition in BeWo human placental choriocarcinoma cells.
  Yuki Miyazawa; Ayako Furugen; Ryoichi Aoyagi; Haruna Kosugi; Ayako Nishimura; Takeshi Umazume; Katsuya Narumi; Masaki Kobayashi
  Toxicology in vitro : an international journal published in association with BIBRA, 105934, 105934, 2024年09月03日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Folates are essential nutrients for fetal development during pregnancy. Valproic acid (VPA), an inhibitor of histone deacetylases (HDACs), alters the expression of folate carriers in placental cells; however, the underlying mechanisms remain unclear. Here, we aimed to determine the profiles of folate carriers (folate receptor alpha [FOLR1], solute carrier [SLC]-19A1, and SLC46A1) after inhibition of HDACs, especially class I and IIa HDACs, using different inhibitors and gene knockdown tests. Quantitative polymerase chain reaction revealed that BeWo cells (a trophoblast model) expressed HDACs and folate carriers, similar to human placental villi. FOLR1 expression was upregulated by VPA, apicidin, and trichostatin A, but downregulated by MS-275 after 24 h treatment. VPA and apicidin upregulated the expression of SLC46A1. These inhibitors downregulated SLC19A1 expression. TMP269 (a class IIa inhibitor) did not affect folate carrier levels. HDAC1/2 knockdown upregulated FOLR1 and SLC46A1 levels, whereas HDAC1/3 knockdown downregulated FOLR1 levels. Our findings suggest that the pharmacological inhibition of class I HDACs alters the expression of folate carriers in BeWo cells. By contrast, HDAC inhibitors exert different regulatory effects on folate carriers. Moreover, HDAC1/2 inhibition may be a potential mechanism involved in altering FOLR1 and SLC46A1 levels.
• Contribution of aldehyde oxidase to methotrexate-induced hepatotoxicity: In Vitro and pharmacoepidemiological approaches.
  Ayako Moriyama; Hinata Ueda; Katsuya Narumi; Shuho Asano; Ayako Furugen; Yoshitaka Saito; Masaki Kobayashi
  Expert opinion on drug metabolism & toxicology, 2024年05月06日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Methotrexate (MTX) is partially metabolized by aldehyde oxidase (AOX) in the liver and its clinical impact remains unclear. In this study, we aimed to demonstrate how AOX contributes to MTX-induced hepatotoxicity in vitro and clarify the relationship between concomitant AOX inhibitor use and MTX-associated liver injury development using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We assessed intracellular MTX accumulation and cytotoxicity using HepG2 cells. We used the FAERS database to detect reporting odds ratio (ROR)-based MTX-related hepatotoxicity event signals. RESULTS: AOX inhibition by AOX inhibitor raloxifene and siRNA increased the MTX accumulation in HepG2 cells and enhanced the MTX-induced cell viability reduction. In the FAERS analysis, the ROR for MTX-related hepatotoxicity increased with non-overlap of 95% confidence interval when co-administered with drugs with higher Imax, u (maximum unbound plasma concentration)/IC50 (half-maximal inhibitory concentration for inhibition of AOX) calculated based on reported pharmacokinetic data. CONCLUSION: AOX inhibition contributed to MTX accumulation in the liver, resulting in increased hepatotoxicity. Our study raises concerns regarding MTX-related hepatotoxicity when co-administered with drugs that possibly inhibit AOX activity at clinical concentrations.
• Monocarboxylate Transporters 1 and 2 Are Responsible for L-Lactate Uptake in Differentiated Human Neuroblastoma SH-SY5Y Cells
  Tomoya Sakuma; Yuto Mukai; Atsushi Yamaguchi; Yudai Suganuma; Keisuke Okamoto; Ayako Furugen; Katsuya Narumi; Shuhei Ishikawa; Yoshitaka Saito; Masaki Kobayashi
  Biological and Pharmaceutical Bulletin, 47, 4, 764, 770, Pharmaceutical Society of Japan, 2024年04月04日, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Evaluation of Prediabetes in Cisplatin-induced Nephrotoxicity in the Short Hydration Method: A Subgroup Analysis
  YOSHITAKA SAITO; TATSUHIKO SAKAMOTO; MASAKI KOBAYASHI; YOH TAKEKUMA; ISSEI HIGUCHI; KEISUKE OKAMOTO; JUN SAKAKIBARA-KONISHI; YASUSHI SHIMIZU; ICHIRO KINOSHITA; MITSURU SUGAWARA
  In Vivo, 38, 2, 800, 806, Anticancer Research USA Inc., 2024年02月28日, ［査読有り］
  研究論文（学術雑誌）
• Breast milk concentrations of acetaminophen and diclofenac - unexpectedly high mammary transfer of the general-purpose drug acetaminophen.
  Ryo Tamaki; Kiwamu Noshiro; Ayako Furugen; Ayako Nishimura; Hiroshi Asano; Hidemichi Watari; Masaki Kobayashi; Takeshi Umazume
  BMC pregnancy and childbirth, 24, 1, 90, 90, 2024年01月29日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Breastfeeding is considered to be the most effective way of ensuring the health and survival of newborns. However, mammary transfer of drugs administered to mothers to breastfeeding infants remains a pressing concern. Acetaminophen and diclofenac sodium are widely prescribed analgesics for postpartum pain relief, but there have been few recent reports on the mammary transfer of these drugs, despite advances in analytic techniques. METHODS: We conducted a study on 20 postpartum mothers from August 2019-March 2020. Blood and milk samples from participants were analyzed using liquid chromatography-electrospray ionization tandem mass spectrometry within 24 hours after oral administration of acetaminophen and diclofenac sodium. The area under the concentration-time curve (AUC) was calculated from the concentration curve obtained by a naive pooled-data approach. RESULTS: For acetaminophen, AUC was 36,053 ng/mL.h and 37,768 ng/mL.h in plasma and breast milk, respectively, with a milk-to-plasma drug concentration ratio of 1.048. For diclofenac, the AUC was 0.227 ng/mL.h and 0.021 ng/mL.h, in plasma and breast milk, respectively, with a milk-to-plasma drug concentration ratio of 0.093. CONCLUSIONS: While diclofenac sodium showed low mammary transfer, acetaminophen showed a relatively high milk-to-plasma drug concentration ratio. Given recent studies suggesting potential connections between acetaminophen use during pregnancy and risks to developmental prognosis in children, we believe that adequate information regarding the fact that acetaminophen is easily transferred to breast milk should be provided to mothers.
• Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy.
  Atsushi Yamaguchi; Yoshitaka Saito; Keisuke Okamoto; Ayako Furugen; Katsuya Narumi; Yoh Takekuma; Jun Sakakibara-Konishi; Yasushi Shimizu; Ichiro Kinoshita; Mitsuru Sugawara; Masaki Kobayashi
  In vivo (Athens, Greece), 38, 6, 2886, 2896, 2024年, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. PATIENTS AND METHODS: This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. RESULTS: In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. CONCLUSION: The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.
• Regulation of Chloride Channels by Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced α-Defensin 5.
  Ippei Uemura; Natsuko Takahashi-Suzuki; Fumiya Kita; Masaki Kobayashi; Takehiro Yamada; Ken Iseki; Takashi Satoh
  Biological & pharmaceutical bulletin, 47, 1, 159, 165, 2024年, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat non-small cell lung cancer with EGFR mutations. However, first-generation erlotinib and second-generation afatinib often cause diarrhea, which may develop because of the association between EGFR-TKIs and the chloride channel or abnormalities in the intestinal microbiota due to disruption of the intestinal immune system. As reports on the effects of EGFR-TKIs on intestinal immunity are lacking, we aimed to determine whether the intestinal immune system is involved in the molecular effects of EGFR-TKIs on chloride channels using Caco-2 cells. Initially, we evaluated the association of chloride channels with α-defensin 5 (DEFA5), a marker of intestinal immunity. Erlotinib and afatinib significantly increased the extracellularly secreted DEFA5 level and autophagy-related 16-like 1 and X-box binding protein 1 transcript levels, indicative of enhanced granule exocytosis. Conversely, intracellular DEFA5 and Toll-like receptor 4 protein expression and tumor necrosis factor-α transcript levels decreased significantly, suggesting that Toll-like receptor 4 suppression repressed DEFA5 production. Furthermore, among the chloride channels, DEFA5 was found to significantly increase the transcript levels of cystic fibrosis transmembrane conductance regulators. These results indicate that DEFA5 plays a significant role in the mechanism of chloride channel-mediated diarrhea induced by EGFR-TKIs. Therefore, we successfully elucidated the potential host action of DEFA5 in cancer therapy for the first time.
• Comparative study on the occurrence of adverse effects in the concomitant use of azathioprine and aldehyde oxidase inhibitors.
  Hinata Ueda; Katsuya Narumi; Shuho Asano; Yoshitaka Saito; Ayako Furugen; Masaki Kobayashi
  Expert opinion on drug safety, 2023年12月14日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVES: Aldehyde oxidase (AO) is a molybdenum-containing redox enzyme similar to xanthine oxidase that is involved in the thiopurine metabolism. This study investigated the effects of drug-drug interactions (DDIs) between azathioprine (AZA) and AO inhibitors on hematologic and hepatic disorders using the U.S. Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report database. METHODS: The presence of DDI was assessed using the interaction signal scores (ISSs) calculated via the reporting odds ratios and 95% confidence intervals. The study used reports of 'azathioprine' as a suspect drug for adverse effects. AO inhibitors were selected based on previous in vitro reports. RESULTS: Some drugs tested positive for ISSs in each database and type of adverse effect (hematologic or hepatic disorder) analysis. Among these drugs, chlorpromazine, clozapine, hydralazine, and quetiapine could inhibit AZA metabolism via AO, given the previously reported clinical blood concentration and inhibitory effects of each drug. CONCLUSION: Concomitant use of AO inhibitors increased the signals for AZA-induced adverse effects. To date, no studies have evaluated the clinical importance of AO as a drug-metabolizing enzyme, and further in vitro and clinical research is needed to clarify the contribution of AO to the pharmacokinetics of thiopurines.
• Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.
  Yuki Ueda; Ayako Furugen; Masaki Kobayashi; Yasuyuki Sato; Yasuhiro Ueda; Asako Hayashi; Takeru Goto; Shuhei Kimura; Masashi Narugami; Sachiko Nakakubo; Midori Nakajima; Kiyoshi Egawa; Takayuki Okamoto; Atsushi Manabe; Hideaki Shiraishi
  Brain & development, 2023年10月30日, ［査読有り］, ［国際誌］
  英語, BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.
• Risk factor analysis for cisplatin-induced nephrotoxicity with the short hydration method in diabetic patients.
  Yoshitaka Saito; Masaki Kobayashi; Shinya Tamaki; Katsuyuki Nakamura; Daisuke Hirate; Kenta Takahashi; Yoh Takekuma; Jun Sakakibara-Konishi; Yasushi Shimizu; Ichiro Kinoshita; Mitsuru Sugawara
  Scientific reports, 13, 1, 17126, 17126, 2023年10月10日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The occurrence of cisplatin (CDDP)-induced nephrotoxicity (CIN) has decreased with advancements in supportive care. In contrast, we reported that baseline diabetes mellitus (DM) complications significantly worsen CIN. This study aimed to determine further risk factors associated with CIN development in DM patients. Patients with thoracic cancer requiring DM pharmacotherapy, who received CDDP (≥ 60 mg/m2)-containing regimens using the short hydration method (n = 140), were enrolled in this retrospective multicenter observational study. The primary endpoint of the present study was the elucidation of risk factors (patient factors, DM medication influence, and treatment-related factors) associated with CIN development in patients with DM. Cisplatin-induced nephrotoxicity occurred in 22.1% of patients with DM. The median worst variation of serum creatinine levels and creatinine clearance (worst level - baseline level) was 0.16 mg/dL (range: - 0.12-1.41 mg/dL) and - 15.9 mL/min (- 85.5-24.3 mL/min), respectively. Multivariate logistic regression analyses identified female sex as the singular risk factor for CIN development in the DM population (adjusted odds ratio; 2.87, 95% confidence interval; 1.08-7.67, P = 0.04). Diabetes mellitus medication and treatment-related factors did not affect CIN development. In conclusion, our study revealed that female sex is significantly associated with CIN development in patients with DM and thoracic cancer.
• Quantitative analysis of communication changes in online medication counseling -Using the Roter Interaction Analysis System.
  Ayako Mori; Izumi Kato; Katsuya Narumi; Yoh Takekuma; Hitoshi Kashiwagi; Yuki Sato; Mitsuru Sugawara; Masaki Kobayashi
  Research in social & administrative pharmacy : RSAP, 2023年10月04日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Quantitative analysis and objective evaluation of communication play an important role in medical communication education. In the process of developing an online methodology for medication counseling practice, we felt the necessity of conducting a quantitative evaluation to enhance its effectiveness. OBJECTIVES: This study aimed to quantitatively evaluate the communication in each scenario to comprehensively identify the differences between face-to-face and online communication in medication counseling practicum. In addition, we examined how patient satisfaction changes between face-to-face and online interactions. METHODS: Face-to-face and online role-playing were conducted between simulated patients (SPs) and students acting as pharmacists, and their dialogues were videotaped. The utterances in each recorded dialogue were categorized and analyzed by the Roter interaction analysis system (RIAS). The Japanese version of the Medical Interview Satisfaction Scale (MISS-21J) responses of the SPs were analyzed for the patient satisfaction survey. RESULT: The results of the RIAS analysis revealed that the socio-emotional category appeared significantly more frequently in face-to-face communication, with more utterances that were more attuned to the feelings of the other person and more considerate of his or her feelings. The ratio of the number of utterances between students and SPs suggested that the communication was more interactive. CONCLUSION: Based on the respective communication tendencies may have led to higher satisfaction in face-to-face than in online patient satisfaction surveys, less anxiety about illness and medications, and easier trusting relationships. Since it is difficult to grasp the mood of the other party and to open up to them due to the lack of nonverbal information in online dialogue, it is necessary to be more conscious of conversations that capture the feelings of patients in online medication counseling.
• Molecular characteristic analysis of single-nucleotide polymorphisms in SLC16A9/hMCT9
  Atsushi Yamaguchi; Yuto Mukai; Tomoya Sakuma; Yudai Suganuma; Ayako Furugen; Katsuya Narumi; Masaki Kobayashi
  Life Sciences, 122205, 122205, Elsevier BV, 2023年10月, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Beneficial effects of a new neuroprotective compound in neuronal cells and MPTP-administered mouse model of Parkinson's disease.
  Izumi Kato; Yudai Ogawa; Fumika Yakushiji; Jiro Ogura; Masaki Kobayashi; Naoya Shindo; Satoshi Ichikawa; Katsumi Maenaka; Masahiro Sakaitani
  Chemical communications (Cambridge, England), 59, 82, 12306, 12309, 2023年09月27日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, A new compound, a derivative of 3,4,5-trimethoxy-N-phenyl benzamide bearing an 8''-methylimidazopyridine moiety, is found to demonstrate neuroprotective effects by preventing cell death caused by oxidative stress. The compound possesses high solubility and metabolic stability, and inhibits MPTP-induced effects in vivo, indicating high potential as a therapeutic drug for Parkinson's disease.
• Development of a risk prediction model for surgical site infection after lower third molar surgery.
  Akira Yamagami; Katsuya Narumi; Yoshitaka Saito; Ayako Furugen; Shungo Imai; Yoshimasa Kitagawa; Yoichi Ohiro; Ryo Takagi; Yoh Takekuma; Mitsuru Sugawara; Masaki Kobayashi
  Oral diseases, 2023年09月27日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: There is little evidence regarding risk prediction for surgical site infection (SSI) after lower third molar (L3M) surgery. METHODS: We conducted a nested case-control study to develop a multivariable logistic model for predicting the risk of SSI after L3M surgery. Data were obtained from Hokkaido University Hospital from April 2013 to March 2020. Multiple imputation was applied for the missing values. We conducted decision tree (DT) analysis to evaluate the combinations of factors affecting SSI risk. RESULTS: We identified 648 patients. The final model retained the available distal space (Pell & Gregory II [p = 0.05], Pell & Gregory III [p < 0.01]), depth (Pell & Gregory B [p < 0.01], Pell & Gregory C [p < 0.01]), surgeon's experience (3-10 years [p = 0.25], <3 years [p < 0.01]), and simultaneous extraction of both L3M [p < 0.01]; the concordance-statistic was 0.72. The DT analysis demonstrated that patients with Pell and Gregory B or C and simultaneous extraction of both L3M had the highest risk of SSI. CONCLUSIONS: We developed a model for predicting SSI after L3M surgery with adequate predictive metrics in a single center. This model will make the SSI risk prediction more accessible.
• Simple and validated method to quantify lacosamide in human breast milk and plasma using UPLC/MS/MS and its application to estimate drug transfer into breast milk.
  Ayako Furugen; Ayako Nishimura; Takeshi Umazume; Hina Ishikawa; Katsuya Narumi; Masaki Kobayashi
  Journal of pharmaceutical health care and sciences, 9, 1, 26, 26, 2023年09月01日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Epilepsy is a common neurological disorder. Lacosamide is a third-generation antiepileptic drug used to treat partial-onset seizures. Limited information is currently available on the transfer of lacosamide to breast milk. To facilitate studies on the safety of lacosamide use during breastfeeding, we aimed to develop a method to quantify lacosamide in human breast milk and plasma using ultra-performance liquid chromatography/tandem mass spectrometry. METHODS: Fifty microliters of breast milk or plasma was used, and samples were prepared by protein precipitation using methanol containing lacosamide-d3 as an internal standard (IS). Chromatography was performed using an ACQUITY HSS T3 column with an isocratic flow of 10 mM ammonium acetate solution/methanol (70:30, v/v). Lacosamide and IS were detected by multiple reaction monitoring in positive ion electrospray mode. The run time was 3.5 min. RESULTS: Calibration curves were linear and in the range of 0.5 to 100 ng/mL both in breast milk and plasma. The validation assessment indicated that precision, accuracy, matrix effects, selectivity, dilution integrity, and stability were acceptable. The developed method was successfully applied to quantify lacosamide in breast milk and plasma obtained from a volunteer who had been orally administered lacosamide twice a day (100 mg × 2). Relative infant dose of lacosamide was estimated to be 14.6% in breast milk at five time points. CONCLUSIONS: We developed a simple and robust method to quantify of lacosamide in human breast milk and plasma. This method could be useful for in future studies investigating the safety of lacosamide use during breastfeeding.
• Atorvastatin Exerts More Selective Inhibitory Effects on hMCT2 than on hMCT1 and hMCT4.
  Atsushi Yamaguchi; Yuto Mukai; Tomoya Sakuma; Ayako Furugen; Katsuya Narumi; Masaki Kobayashi
  Anticancer research, 43, 7, 3015, 3022, 2023年07月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Human monocarboxylate transporter 1 (hMCT1), hMCT2, and hMCT4 transport monocarboxylates, such as L-lactate and pyruvate, with pH dependency. They are often over-expressed in various cancer cells and mediate the energy balance and pH homeostasis. Therefore, hMCT inhibitors can potentially be used as anticancer drugs. However, isoform-selective inhibitors have not yet been well-characterized. In addition, several statins and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors have been reported to inhibit hMCTs, but their selectivity has not yet been evaluated. In this study, we aimed to determine whether statins could inhibit hMCT1, hMCT2, and hMCT4. MATERIALS AND METHODS: We expressed hMCT1, hMCT2, and hMCT4 in a heterologous expression system of Xenopus oocytes and performed inhibitory experiments with various statins (fluvastatin, atorvastatin, simvastatin, rosuvastatin, pravastatin, and pitavastatin). As the three-dimensional structure of hMCT2 has been recently reported, docking simulations of statins and their structures were also performed to estimate the inhibition site. RESULTS: All statins inhibited the transport activities of hMCT1, hMCT2, and hMCT4. In addition, atorvastatin was found to be a potent isoform-selective inhibitor of hMCT2. Docking simulation indicated that atorvastatin could interact with a site surrounded by transmembrane (TM)-2, TM11, and intracellular helix in the TM6/7loop. Therefore, targeting this site may lead to the discovery of more potent hMCT2-selective inhibitors. CONCLUSION: Atorvastatin exerts selective inhibitory effects on hMCT2. These findings provide insights into the inhibitory mechanism of statins against hMCT1, hMCT2, and hMCT4 and may aid in the development of novel anticancer agents.
• Effects of valproic acid on syncytialization in human placental trophoblast cell lines.
  Nanami Ohyama; Ayako Furugen; Riko Sawada; Ryoichi Aoyagi; Ayako Nishimura; Takeshi Umazume; Katsuya Narumi; Masaki Kobayashi
  Toxicology and applied pharmacology, 474, 116611, 116611, 2023年06月27日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, The placenta is a critical organ for fetal development and a healthy pregnancy, and has multifaceted functions (e.g., substance exchange and hormone secretion). Syncytialization of trophoblasts is important for maintaining placental functions. Epilepsy is one of the most common neurological conditions worldwide. Therefore, this study aimed to reveal the influence of antiepileptic drugs, including valproic acid (VPA), carbamazepine, lamotrigine, gabapentin, levetiracetam, topiramate, lacosamide, and clobazam, at clinically relevant concentrations on syncytialization using in vitro models of trophoblasts. To induce differentiation into syncytiotrophoblast-like cells, BeWo cells were treated with forskolin. Exposure to VPA was found to dose-dependently influence syncytialization-associated genes (ERVW-1, ERVFRD-1, GJA1, CGB, CSH, SLC1A5, and ABCC4) in differentiated BeWo cells. Herein, the biomarkers between differentiated BeWo cells and the human trophoblast stem model (TSCT) were compared. In particular, MFSD2A levels were low in BeWo cells but abundant in TSCT cells. VPA exposure affected the expression of ERVW-1, ERVFRD-1, GJA1, CSH, MFSD2A, and ABCC4 in differentiated cells (ST-TSCT). Furthermore, VPA exposure attenuated BeWo and TSCT cell fusion. Finally, the relationships between neonatal/placental parameters and the expression of syncytialization markers in human term placentas were analyzed. MFSD2A expression was positively correlated with neonatal body weight, head circumference, chest circumference, and placental weight. Our findings have important implications for better understanding the mechanisms of toxicity of antiepileptic drugs and predicting the risks to placental and fetal development.
• Association between α-defensin 5 and the expression and function of P-glycoprotein in differentiated intestinal Caco-2 cells.
  Genki Yasuda; Atsuhito Kubota; Keisuke Okamoto; Katsuya Narumi; Ayako Furugen; Izumi Kato; Ayako Mori; Yoshitaka Saito; Takashi Satoh; Natsuko Takahashi-Suzuki; Ken Iseki; Masaki Kobayashi
  Biopharmaceutics & drug disposition, 2023年06月05日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, α-Defensin 5 is known to be secreted by Paneth cells in the small intestine and plays an important role in eliminating pathogenic microorganisms. It has been reported that a decrease in α-defensin 5 level in the human small intestine is a risk of inflammatory bowel disease (IBD). Furthermore, P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter superfamily, encoded by the ABCB1/MDR1 gene, plays an important role in the front line of host defense by protecting the gastrointestinal barrier from xenobiotic accumulation and may contribute to the development and persistence of IBD. Therefore, we examined the relationship between α-defensin 5 and the expression and function of P-gp using a human gastrointestinal model cell line (Caco-2). We found that MDR1 mRNA and P-gp protein level were increased in Caco-2 cells as well as α-defensin 5 secretion corresponded with the duration of cell culture. Exposure to α-defensin 5 peptide and recombinant tumor necrosis factor-α (TNF-α) significantly increased the expression and function P-gp. The mRNA levels of interleukin (IL)-8, IL-6, TNF-α, IL-1β, and IL-2 were also increased following exposure to TNF-α, similar to α-defensin 5 treatment. These results suggest that α-defensin 5 regulates P-gp expression and function by increasing TNF-α expression in Caco-2 cells.
• 5-Oxoproline Enhances 4-Hydroxytamoxifen-induced Cytotoxicity by Increasing Oxidative Stress in MCF-7 Breast Cancer Cells.
  Takanobu Nadai; Katsuya Narumi; Yuto Mukai; Hinata Ueda; Ayako Furugen; Yoshitaka Saito; Masaki Kobayashi
  Anticancer research, 43, 3, 1113, 1120, 2023年03月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Monocarboxylate transporters (MCTs) transport short-chain monocarboxylates, such as lactate, and have been reported to be related to poor prognosis in breast cancer. Our previous studies showed that a high glucose state altered MCT expression and changed the sensitivity of the tamoxifen active metabolite 4-hydroxytamoxifen (4-OHT) via hypoxia-inducible factor-1α (HIF-1α) protein expression. We hypothesized that MCT inhibitors affect 4-OHT-induced cytotoxicity under normal glucose conditions by decreasing HIF-1α protein expression. To test this hypothesis, we evaluated the combined effect of MCT inhibitor and 4-OHT using the estrogen receptor (ER)-positive breast cancer cell line MCF-7, under normal glucose conditions. MATERIALS AND METHODS: Expression of MCTs and oxidative stress markers was evaluated by real-time PCR. Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Reactive oxygen species (ROS) were measured using the cell permeability probe 2',7'-dichlorodihydrofluorescein diacetate. RESULTS: MCT1 expression increased under normal glucose conditions. The MCT1 substrate/inhibitor, 5-oxoproline (5-OP), enhanced 4-OHT-induced cytotoxicity. Bindarit, a selective MCT4 inhibitor, decreased 4-OHT sensitivity, similar to results of our previous study under high glucose conditions. In contrast, the combination of 5-OP and 4-OHT decreased ATP levels compared with that by 4-OHT alone in MCF-7 cells. Furthermore, 5-OP significantly increased the ROS production induced by 4-OHT. CONCLUSION: 5-OP enhances 4-OHT-induced cytotoxicity in ER-positive breast cancer cells under normal glucose conditions.
• Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia
  Atsushi Yamaguchi; Yuto Mukai; Tomoya Sakuma; Katsuya Narumi; Ayako Furugen; Yuma Yamada; Masaki Kobayashi
  Scientific Reports, 13, 1, Springer Science and Business Media LLC, 2023年01月27日, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）, Abstract
  
  Metabolic reprogramming of cancer cells is a potential target for cancer therapy. It is also known that a hypoxic environment, one of the tumor microenvironments, can alter the energy metabolism from oxidative phosphorylation to glycolysis. However, the relationship between hypoxia and drug sensitivity, which targets energy metabolism, is not well known. In this study, A549 cells, a cell line derived from lung adenocarcinoma, were evaluated under normoxia and hypoxia for the sensitivity of reagents targeting oxidative phosphorylation (metformin) and glycolysis (α-cyano-4-hydroxycinnamic acid [CHC]). The results showed that a hypoxic environment increased the expression levels of monocarboxylate transporter (MCT) 4 and hypoxia-induced factor-1α (HIF-1α), whereas MCT1 and MCT2 expression did not vary between normoxia and hypoxia. Furthermore, the evaluation of the ATP production ratio indicated that glycolysis was enhanced under hypoxic conditions. It was then found that the sensitivity to metformin decreased while that to CHC increased under hypoxia. To elucidate this mechanism, MCT4 and HIF-1α were knocked down and the expression level of MCT4 was significantly decreased under both conditions. In contrast, the expression of HIF-1α was decreased by HIF-1α knockdown and increased by MCT4 knockdown. In addition, changes in metformin and CHC sensitivity under hypoxia were eliminated by the knockdown of MCT4 and HIF-1α, suggesting that MCT4 is involved in the phenomenon described above. In conclusion, it was shown that the sensitivity of reagents targeting energy metabolism is dependent on their microenvironment. As MCT4 is involved in some of these mechanisms, we hypothesized that MCT4 could be an important target molecule for cancer therapy.
• Oral administration of linoleic acid immediately before glucose load ameliorates postprandial hyperglycemia.
  Yuta Yamamoto; Katsuya Narumi; Naoko Yamagishi; Toshio Nishi; Takao Ito; Ken Iseki; Masaki Kobayashi; Yoshimitsu Kanai
  Frontiers in pharmacology, 14, 1197743, 1197743, 2023年, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Introduction: Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120. Pretreatment with GPR40 agonists enhanced the secretion of insulin in response to elevating blood glucose levels after glucose load in a diabetes model, but pretreatment with GPR120 agonist did not ameliorate postprandial hyperglycemia. This study examined whether oral administration of linoleic acid (LA), a GPR40 and GPR120 agonist, immediately before glucose load would affect the elevation of postprandial blood glucose levels in rats. Methods: Male rats and rats with type 1 diabetes administered streptozocin were orally administered LA, trilinolein, α-linolenic acid (α-LA), oleic acid, TAK-875, or TUG-891 immediately before glucose load. Blood glucose levels were measured before, then 15, 30, 60 and 120 min after glucose load. CACO-2 cells were used to measure the uptake of [14C] α-MDG for 30 min with or without LA. Gastric content from rats administered LA was collected 15 and 30 min after glucose load, and blood samples were collected for measurement of glucagon-like peptide 1 (GLP-1) and cholecystokinin concentrations. Results: The elevation of postprandial blood glucose levels was slowed by LA but not by trilinolein in rats without promotion of insulin secretion, and this effect was also observed in rats with type 1 diabetes. The uptake of α-MDG, an SGLT-specific substrate, was, however, not inhibited by LA. Gastric emptying was slowed by LA 15 min after glucose load, and GLP-1, but not cholecystokinin, level was elevated by LA 15 min after glucose load. TUG-891, a GPR120 agonist, ameliorated postprandial hyperglycemia but TAK-875, a GPR40 agonist, did not. Pretreatment with AH7614, a GPR120 antagonist, partially canceled the improvement of postprandial hyperglycemia induced by LA. α-LA, which has high affinity with GPR120 as well as LA, slowed the elevation of postprandial blood glucose levels, but oleic acid, which has lower affinity with GPR120 than LA, did not. Conclusion: Oral administration of LA immediately after glucose load ameliorated postprandial hyperglycemia due to slowing of gastric emptying via promotion of GLP-1 secretion. The mechanisms may be associated with GPR120 pathway.
• Diabetes mellitus degenerates cisplatin-induced nephrotoxicity in short hydration method: a propensity score-matching analysis.
  Yoshitaka Saito; Tatsuhiko Sakamoto; Yoh Takekuma; Masaki Kobayashi; Keisuke Okamoto; Naofumi Shinagawa; Yasushi Shimizu; Ichiro Kinoshita; Mitsuru Sugawara
  Scientific Reports, 12, 1, 21819, 21819, 2022年12月17日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method; however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mg/m2)-containing regimens with a short hydration method (n = 227) were retrospectively evaluated. The patients were divided into control and baseline DM complication groups. The primary endpoint was the evaluation of CIN incidence between the groups. Propensity score-matching was performed to confirm the robustness of the primary analysis results. CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in all-patient populations (P = 0.001). In addition, variation of serum creatinine and creatinine clearance significantly worsened in DM patients. Similar results were obtained in a propensity-matched population. Multivariate logistic regression analysis found that DM complication is a singular risk factor for CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62-11.50, P = 0.003). In conclusion, our study revealed that baseline DM complications significantly worsen CIN.
• Association between skin immune-related adverse events (irAEs) and multisystem irAEs during PD-1/PD-L1 inhibitor monotherapy.
  Atsushi Yamaguchi; Yoshitaka Saito; Katsuya Narumi; Ayako Furugen; Yoh Takekuma; Naofumi Shinagawa; Yasushi Shimizu; Hirotoshi Dosaka-Akita; Mitsuru Sugawara; Masaki Kobayashi
  Journal of cancer research and clinical oncology, 149, 4, 1659, 1666, 2022年11月08日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, PURPOSE: Patients treated with immune checkpoint inhibitors (ICIs) often develop immune-related adverse events (irAEs) in various organs of the body. However, the patient factors associated with the development of multisystem irAEs are not well known. Skin irAEs most frequently occur and appear early after ICI treatment initiation. They may be a predictive marker for the development of multisystem irAEs, and their occurrence should be evaluated. METHODS: Data of patients receiving ICI monotherapy for lung cancer, melanoma, and head and neck cancer treatment were retrospectively evaluated (n = 207); the single irAE development group (n = 69) was compared with the multisystem irAE development group (n = 37). The primary endpoint was the comparison of the incidence of skin irAEs between the two groups. RESULTS: Skin, thyroid, and hepatic irAEs were associated with the development of multisystem irAEs (odds ratio: 3.30, 95% confidence interval: 1.27-8.52, p = 0.01 for skin; 5.07, 2.09-12.3, p = 0.0003 for thyroid; 10.63, 1.19-94.7, p = 0.03 for hepatic). Skin irAEs were the most common type (65.0% of total participants) and appeared earlier than other irAEs, except for gastrointestinal and ocular irAEs (median time to onset of skin irAEs: 7.5 weeks). Skin irAEs occurred more frequently in the multisystem irAE group (81.0%) than in the single irAE group (56.5%, p = 0.02). CONCLUSION: Skin irAEs can be a useful predictive marker for multisystem irAE development due to ICI treatment. Consequently, patients with skin irAEs should be treated and monitored for other types of irAEs.
• Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line.
  Yuto Mukai; Atsushi Yamaguchi; Tomoya Sakuma; Takanobu Nadai; Ayako Furugen; Katsuya Narumi; Masaki Kobayashi
  Biopharmaceutics & drug disposition, 43, 5, 183, 191, 2022年09月14日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Fourteen isoforms of the monocarboxylate transporter (MCT) have been reported. Among the MCT isoforms, MCT1, MCT2, and MCT4 play a role in l-lactate/proton co-transport and are involved in the balance of intracellular energy and pH. Therefore, MCT1, MCT2, and MCT4 are associated with energy metabolism processes in normal and pathological cells. In the present study, we evaluated the expression of MCT1, MCT2, and MCT4 and the contribution of these three MCT isoforms to l-lactate uptake in hepatocellular carcinoma (HCC) cells. In HepG2 and Huh-7 cells, l-lactate transport was pH-dependent, which is characteristic of MCT1, MCT2, and MCT4. Furthermore, l-lactate uptake was selectively inhibited by MCT1 and MCT4 inhibitors in HepG2 and Huh-7 cells. Kinetic analysis of HepG2 cells demonstrated that l-lactate uptake was biphasic. Although the knockdown of MCT1 and MCT4 in the HepG2 cells decreased the uptake of l-lactate, the knockdown of MCT2 had no effect on the uptake of l-lactate. Consequently, we concluded that both MCT1 and MCT4 were involved in the transport of l-lactate in HepG2 and Huh-7 cells at pH 6.0. In contrast, PXB-cells, freshly isolated hepatocytes from humanized mouse livers, showed lower MCT4 expression and l-lactate uptake at pH 6.0 compared to that in HCC cell lines. In conclusion, MCT4, which contributes to l-lactate transport in HCC cells, is significantly different in HCC compared to normal hepatocytes, and has potential as a target for HCC treatment. This article is protected by copyright. All rights reserved.
• The rs35217482 (T755I) single-nucleotide polymorphism in aldehyde oxidase-1 attenuates protein dimer formation and reduces the rates of phthalazine metabolism
  Hinata Ueda; Katsuya Narumi; Ayako Furugen; Yoshitaka Saito; Masaki Kobayashi
  Drug Metabolism and Disposition, DMD, AR, American Society for Pharmacology & Experimental Therapeutics (ASPET), 2022年07月16日, ［査読有り］, ［最終著者, 責任著者］
  研究論文（学術雑誌）
• Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.
  Yoshitaka Saito; Yoh Takekuma; Masaki Kobayashi; Naofumi Shinagawa; Takuro Noguchi; Satoshi Takeuchi; Yasushi Shimizu; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Mitsuru Sugawara
  Anticancer research, 42, 6, 3185, 3193, 2022年06月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.
• Uptake of antiepileptic drugs in forskolin-induced differentiated BeWo cells: Alteration of gabapentin transport.
  Mai Koishikawa; Ayako Furugen; Nanami Ohyama; Katsuya Narumi; Shuhei Ishikawa; Masaki Kobayashi
  Xenobiotica; the fate of foreign compounds in biological systems, 52, 4, 1, 30, 2022年06月01日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Previous studies have indicated that the expression levels of several transporters are altered during placental trophoblast differentiation. However, changes in the transport activities of therapeutic agents during differentiation must be comprehensively characterised. Antiepileptic drugs, including gabapentin (GBP), lamotrigine (LTG), topiramate, and levetiracetam, are increasingly prescribed during pregnancy. The objective of this study was to elucidate differences in the uptake of antiepileptic drugs during the differentiation process.Human placental choriocarcinoma BeWo cells were used as trophoblast models. For differentiation into syncytiotrophoblast-like cells, cells were treated with forskolin.The uptake of GBP and LTG was lower in differentiated BeWo cells than in undifferentiated cells. In particular, the maximum uptake rate of GBP transport was decreased in differentiated BeWo cells. Furthermore, GBP transport was trans-stimulated by the amino acids His and Met. We investigated the profiles of amino acids in undifferentiated and differentiated BeWo cells. Supplementation with His and Met, which demonstrated trans-stimulatory effects on GBP uptake, restored GBP uptake in differentiated cells. The findings of this study suggest that drug transport in BeWo cells can be altered before and after differentiation, and that the altered GBP uptake could be mediated by the intracellular amino acid status.
• Evaluation of the strategies to reduce third-generation oral cephalosporins in dentistry at a Japanese academic hospital: An interrupted time series analysis.
  Akira Yamagami; Katsuya Narumi; Yoshitaka Saito; Ayako Furugen; Shungo Imai; Yoshimasa Kitagawa; Yoichi Ohiro; Ryo Takagi; Yoh Takekuma; Mitsuru Sugawara; Masaki Kobayashi
  Journal of clinical pharmacy and therapeutics, 47, 7, 1010, 1019, 2022年03月07日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, WHAT IS KNOWN AND OBJECTIVE: Third-generation oral cephalosporins, especially cefcapene-pivoxil (CFPN-PI), have been used frequently in the Japanese dental field. In December 2014 and April 2016, the newly published clinical guidelines recommended the use of amoxicillin (AMPC). Thus, it is important to evaluate the impact of these guidelines on the prescription profiles of prophylactic antibiotics, clinical outcomes and cost-effectiveness of antibiotics. METHODS: We conducted a retrospective study to analyse an interrupted time series analysis from April 2013 to March 2020 at the Department of Dentistry of Hokkaido University Hospital. A segmented regression model was used to estimate the changes in the incidence of infectious complications following tooth extraction. Prescribed antibiotic data were evaluated via days of therapy (DOT). Antibiotic costs were calculated in terms of the Japanese yen (JPY). RESULTS AND DISCUSSION: We identified 17,825 eligible patients. The incidence rates of infectious complications (SSI + dry socket) and SSI after tooth extraction were 3.2% and 2.2%, respectively, during the entire period. The extraction of impacted third molars corresponded to 5.0% and 3.4%, respectively. However, their incidence rates were not significantly different during this period. The use of prophylactic antibiotics and antibiotic cost showed consistent trends following the implementation of guidelines. The mean DOT of CFPN-PI decreased (ranging from 4893.6 DOTs/1000 patients [March 2013 to November 2014] to 3856.4 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3856.4 DOTs/1000 patients [December 2014 to March 2016] to 2293.9 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). In contrast, the mean DOT of AMPC was found to be increased (ranging from 1379.7 DOTs/1000 patients [March 2013 to November 2014] to 3236.3 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3236.3 DOTs/1000 patients [December 2014 to March 2016] to 4597.8 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). The mean monthly cost was decreased (ranging from 905.3 JPY [March 2013 to November 2014] to 788.7 JPY [December 2014 to March 2016]; p = 0.003, and from 788.7 JPY [December 2014 to March 2016] to 614.0 JPY [April 2016 to March 2020]; p < 0.001). WHAT IS NEW AND CONCLUSION: After December 2014, prophylactic antibiotics were switched from CFPN-PI to AMPC, and the incidence rate of infectious complications was not significantly different over time. However, changing antibiotics is useful from a cost-effectiveness perspective.
• 5-Aminosalicylic Acid, A Weak Agonist for Aryl Hydrocarbon Receptor That Induces Splenic Regulatory T Cells.
  Atsuhito Kubota; Masaru Terasaki; Rie Takai; Masaki Kobayashi; Ryuta Muromoto; Hiroyuki Kojima
  Pharmacology, 107, 1-2, 1, 7, 2021年12月16日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, INTRODUCTION: 5-Aminosalicylic acid (5-ASA) is widely used as a key drug in inflammatory bowel disease. It has been recently reported that 5-ASA induces CD4 + Foxp3 + regulatory T cells (Tregs) in the colon via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that regulates inflammation. However, the role of 5-ASA as an AhR agonist that induces Tregs in the spleen remains unknown. METHODS: In the present study, we investigated these themes using an AhR-mediated transactivation assay and flow cytometry analysis. The experiments were conducted by using DR-EcoScreen cells and C57BL/6 mice. RESULTS: The DR-EcoScreen cell-based transactivation assay revealed that 5-ASA acted as a weak AhR agonist at concentrations of ≥300 μM (1.31-1.45-fold), and that a typical AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), activated AhR at a concentration of 0.1 nM (22.8-fold). In addition, the treatment of mouse splenic cells with 300 μM 5-ASA in a primary culture assay significantly induced CD4+CD25 + Foxp3 + Tregs (control vs. 5-ASA: 9.0% vs. 12.65%, p < 0.05), while 0.1 nM TCDD also showed significant induction of Tregs (control vs. TCDD: 9.0% vs. 14.1%, p < 0.05). Interestingly, this induction was eliminated by co-treatment with an AhR antagonist, CH-223191. DISCUSSION: These results suggest that 5-ASA is a weak agonist of AhR and thereby induces Tregs in spleen cells. Our findings may provide useful insights into the mechanism by which 5-ASA regulates inflammation.
• Diclofenac potentiates the antitumor effect of cisplatin in a xenograft mouse model transplanted with cisplatin-resistant cells without enhancing cisplatin-induced nephrotoxicity.
  Keisuke Okamoto; Hinata Ueda; Yoshitaka Saito; Katsuya Narumi; Ayako Furugen; Masaki Kobayashi
  Drug metabolism and pharmacokinetics, 41, 100417, 100417, 2021年08月16日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Cisplatin (CDDP) is a well-known anticancer agent, and CDDP-induced nephrotoxicity (CIN) is one of the most serious adverse effects. Previously, we revealed that while celecoxib reduces CIN, diclofenac does not appear to enhance it. Furthermore, we reported that diclofenac additively enhances the cytotoxic effect of CDDP on CDDP-resistant A549 cells (A549/DDP cells) and their spheroids. In addition, celecoxib reduces the cytotoxic effect of CDDP on A549/DDP cells while demonstrating an anticancer effect; however, it enhanced the effect of CDDP cytotoxicity on spheroids. Therefore, we evaluated the effects of diclofenac or celecoxib on CIN and the antitumor effect of CDDP in a xenograft mouse model transplanted with A549/DDP cells. Although CDDP did not decrease tumor size and tumor weight, these parameters were significantly reduced following co-administration with diclofenac when compared with the control group. Conversely, celecoxib marginally suppressed the antitumor effect of CDDP. Moreover, CDDP increased the mRNA levels of kidney injury molecule 1 (Kim-1), a renal disorder marker, in the kidneys of xenograft mice; treatment with celecoxib and diclofenac did not impact Kim-1 mRNA levels increased by CDDP. In conclusion, diclofenac potentiated the antitumor effect of CDDP without enhancing CIN.
• In vitro and in vivo evaluation of organic anion-transporting polypeptide 2B1-mediated pharmacokinetic interactions by apple polyphenols.
  Yuka Takahashi; Katsuya Narumi; Takanobu Nadai; Hinata Ueda; Taiki Yamamura; Ayako Furugen; Masaki Kobayashi
  Xenobiotica; the fate of foreign compounds in biological systems, 51, 11, 1, 36, 2021年08月16日, ［査読有り］, ［最終著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Organic anion-transporting polypeptide (OATP) 2B1 plays a critical role in the intestinal absorption of substrate drugs. Apple juice reportedly interacts with OATP2B1 substrate drugs. The purpose of this study was to investigate the effect of two apple polyphenols, phloretin and phloridzin, on OATP2B1-mediated substrate transport in vitro and to evaluate the effect of phloretin on rosuvastatin pharmacokinetics in rats.In vitro studies revealed that both polyphenols inhibited OATP2B1-mediated uptake of estrone-3-sulfate. Despite preincubation with phloretin and subsequent washing, the inhibitory effect was retained. Phloretin markedly decreased OATP2B1-mediated rosuvastatin uptake, with an IC50 value of 3.6 μM.On coadministering rosuvastatin and phloretin in rats, the plasma concentration of rosuvastatin 10 min after oral administration was significantly lower than that in the vehicle group. The area under the plasma concentration-time curve of rosuvastatin was not significant, showing a tendency to decrease in the phloretin group when compared with the vehicle group. The in-situ rat intestinal loop study revealed the inhibitory effect of phloretin on rosuvastatin absorption.Phloretin has potent and long-lasting inhibitory effects on OATP2B1 in vitro. Phloretin may inhibit OATP2B1-mediated intestinal absorption of rosuvastatin; however, it failed to significantly impact the systemic exposure of rosuvastatin in rats.
• Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats.
  Keisuke Okamoto; Fumi Kitaichi; Yoshitaka Saito; Hinata Ueda; Katsuya Narumi; Ayako Furugen; Masaki Kobayashi
  European journal of pharmacology, 909, 174395, 174395, 2021年07月29日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics.
• Kinetic analysis of cystine uptake and inhibition pattern of sulfasalazine in A549 cells.
  Keisuke Okamoto; Yoshitaka Saito; Hinata Ueda; Katsuya Narumi; Ayako Furugen; Masaki Kobayashi
  Biopharmaceutics & drug disposition, 42, 8, 389, 392, 2021年07月20日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Cystine/glutamate transporter (xCT) is an antiporter involved in cystine uptake and glutamate efflux. However, there are very few reports regarding the kinetic analysis of xCT for cystine uptake using cancer cell lines, as well as the inhibition pattern of sulfasalazine, an inhibitor of xCT, for cystine uptake. Therefore, the purpose of this study was to clarify the kinetics of xCT in A549 cells, human lung cancer cells, and to reveal the inhibition pattern of sulfasalazine. Cystine uptake occurred in a time-dependent manner, with linear cystine uptake observed for 5 min. Additionally, sulfasalazine inhibited cystine uptake in a concentration-dependent manner, presenting an IC50 value of 24.7 ± 5.6 μM. Cystine uptake was saturated with increasing concentration, demonstrating Km and Vmax values of 179.4 ± 26.7 μM and 30.4 ± 2.3 nmol/min/mg protein, respectively. Moreover, during cystine uptake with sulfasalazine, Km and Vmax were >300 μM and 8.0 ± 1.5 nmol/min/mg protein, respectively, suggesting that sulfasalazine might demonstrate a mixed inhibition pattern. Furthermore, xCT siRNA decreased the xCT mRNA level and reduced cystine uptake. In conclusion, xCT was involved in the cystine uptake in A549 cells and sulfasalazine showed a mixed inhibition pattern to xCT.
• Risk factor analysis for taxane-associated acute pain syndrome under the dexamethasone prophylaxis.
  Yoshitaka Saito; Yoh Takekuma; Masaki Kobayashi; Tatsuhiko Sakamoto; Hiroko Yamashita; Mitsuru Sugawara
  Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 29, 12, 8059, 8067, 2021年07月06日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. METHODS: In total, 143 patients with breast cancer who received docetaxel (75 mg/m2) or paclitaxel (175 mg/m2)-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of ≥ G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. RESULTS: Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of ≥ G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of ≥ G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of ≥ G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. CONCLUSION: Pegfilgrastim co-administration is an independent risk factor for ≥ G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.
• Preexisting autoimmune disease is a risk factor for immune-related adverse events: a meta-analysis.
  Atsushi Yamaguchi; Yoshitaka Saito; Keisuke Okamoto; Katsuya Narumi; Ayako Furugen; Yoh Takekuma; Mitsuru Sugawara; Masaki Kobayashi
  Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 2021年06月23日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: Patients with preexisting autoimmune disease (PAD) are often excluded from clinical trials assessing immune checkpoint inhibitors (ICIs). Therefore, the safety of ICI therapy in patients with PAD remains unclear. Herein, we evaluated the incidence of immune-related adverse events (irAEs) in patients with PAD when compared with non-PAD patients. METHODS: We searched MEDLINE/PubMed, Web of Science, and Google Scholar for eligible studies from inception to January 2021. Observational studies reporting the incidence of irAEs in patients with and without PAD were included. We then performed a meta-analysis of eligible studies using forest plots. The primary endpoint of this study was the incidence rate of irAEs between patients with and without PAD. RESULTS: We identified three prospective and three retrospective studies involving 206 patients with PAD and 3078 patients without PAD. In the meta-analysis, 128 patients with PAD (62.1%) experienced irAEs, which occurred in 51.9% of non-PAD patients, resulting in an odds ratio (OR) of 2.14 (95% confidence interval [CI] 1.58-2.89). In the subgroup analysis, the incidence of irAEs was significantly higher in patients with PAD (OR = 2.19, 95% CI [1.55-3.08]). Furthermore, no significant heterogeneity or publication bias was detected, indicating that our meta-analysis could be generalized to clinical settings. CONCLUSION: This meta-analysis demonstrated that PAD was a risk factor for irAE incidence. These results suggest that monitoring the occurrence of irAEs in patients with PAD is required to manage irAEs appropriately.
• Effects of valproate, an HDAC inhibitor, on the expression of folate carriers and folate metabolism-related genes in the placenta of rats.
  Ayako Furugen; Yuki Kanno; Nanami Ohyama; Yuko Kurosawa; Naoko Jinno; Katsuya Narumi; Ken Iseki; Masaki Kobayashi
  Drug metabolism and pharmacokinetics, 40, 100409, 100409, 2021年06月07日, ［査読有り］, ［最終著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Valproate (VPA), an antiepileptic drug, is known to inhibit histone deacetylases (HDACs). Exposure to VPA during pregnancy increases several fetal risks. The maintenance of folate level during pregnancy is essential for adequate fetal development, and the placenta plays a critical role in supplying nutrients to the fetus. The aim of this study was to elucidate the effects of VPA on the gene expression of folate carriers and metabolizing enzymes in the rat placenta at both mid and late gestation periods. Pregnant rats were orally administered VPA on a single day or 4 days (repeated administration). Gene expression of folate carriers (Folr1, Slc19a1, Slc46a1) and metabolizing enzymes (Cth, Mtr, Mtrr, Mthfr, Dhfr) was assessed in the placenta on gestational day (GD) 13 or GD20. In the control rats, the expression of Folr1, Slc46a1, Cth, and Mthfr tended to be upregulated, whereas that of Mtrr and Dhfr was downregulated during gestation; the expression of Slc19a1 and Mtr did not change. Repeated VPA administration reduced the placental expression of Folr1and Mtr on GD20 and increased the expression of Dhfr on GD13 compared with the control. These findings indicate that administration of VPA alters the placental gene expression of folate carriers and metabolism-related enzymes.
• Characterization of deoxyribonucleoside transport mediated by concentrative nucleoside transporters.
  Taiki Yamamura; Katsuya Narumi; Tsukika Ohata; Hiroshi Satoh; Takao Mori; Ayako Furugen; Masaki Kobayashi; Ken Iseki
  Biochemical and biophysical research communications, 558, 120, 125, 2021年04月25日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize CNT-subtype specificity to understand the systemic disposition of deoxyribonucleosides (dNs) and their analogs, the involvement of CNTs in transporting dNs is not fully understood. In this study, using COS-7 cells that transiently expressed CNT1, CNT2, or CNT3, we investigated if CNTs could transport not only ribonucleosides but also dNs, i.e., 2'-deoxyadenosine (dAdo), 2'-deoxyguanosine (dGuo), and 2'-deoxycytidine (dCyd). The cellular uptake study demonstrated that dAdo and dGuo were taken up by CNT2 but not by CNT1. Although dCyd was taken up by CNT1, no significant uptake was detected in COS-7 cells expressing CNT2. Similarly, these dNs were transported by CNT3. The apparent Km values of their uptake were as follows: CNT1, Km ＝ 141 μM for dCyd; CNT2, Km ＝ 62.4 μM and 54.9 μM for dAdo and dGuo, respectively; CNT3, Km ＝ 14.7 μM and 34.4 μM for dGuo and dCyd, respectively. These results demonstrate that CNTs contribute not only to ribonucleoside transport but also to the transport of dNs. Moreover, our data indicated that CNT1 and CNT2 selectively transported pyrimidine and purine dNs, respectively, and CNT3 was shown to transport both pyrimidine and purine dNs.
• Transport function, regulation, and biology of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4).
  Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Pharmacology & therapeutics, 226, 107862, 107862, 2021年04月21日, ［査読有り］, ［筆頭著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4) are involved in the proton-dependent transport of monocarboxylates such as L-lactate, which play an essential role in cellular metabolism and pH regulation. hMCT1 and 4 are overexpressed in a number of cancers, and polymorphisms in hMCT1 have been reported to be associated with the prognosis of some cancers. Accordingly, recent advances have focused on the inhibition of these transporters as a novel therapeutic strategy in cancers. To screen for MCT inhibitors for clinical application, it is important to study MCT function and regulation, and the effect of compounds on them, using human-derived cells. In this review, we focus on the transport function, regulation, and biology of hMCT1 and hMCT4, and the effects of genetic variation in these transporters in humans.
• The association between SLC16A11 haplotype and lipid metabolism in Japanese patients with type 2 diabetes.
  Yuki Kimura; Issei Higuchi; Masaki Kobayashi; Ayako Furugen; Katsuya Narumi; Yuya Suzuki; Hideaki Miyoshi; Akinobu Nakamura; Tatsuya Atsumi; Ken Iseki
  Drug metabolism and pharmacokinetics, 37, 100376, 100376, 2021年04月, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Solute carrier (SLC) 16A11 has been reported as a risk gene for type 2 diabetes (T2D). However, the physiological function of SLC16A11 has not yet been clarified, and the relationship between SLC16A11 and T2D condition remains unclear. Therefore, we performed an association analysis between the SLC16A11 genotype and T2D pathology. The SLC16A11 genotype was determined by direct sequencing in 85 Japanese patients with T2D. The genotypes were analyzed by Mann-Whitney's U test and Chi-square test. Six single nucleotide polymorphisms (SNPs) were detected in the SLC16A11 gene, and five of them formed a haplotype (5SNP haplotype). The 5SNP haplotype carriers had significantly higher fasting plasma glucose (FPG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) than the noncarriers. The SLC16A11 genotype affected the values of laboratory parameters for T2D, particularly of blood lipids. The function of SLC16A11 may be related to lipid metabolism.
• Anticancer effects of non-steroidal anti-inflammatory drugs against cancer cells and cancer stem cells.
  Keisuke Okamoto; Yoshitaka Saito; Katsuya Narumi; Ayako Furugen; Ken Iseki; Masaki Kobayashi
  Toxicology in vitro : an international journal published in association with BIBRA, 74, 105155, 105155, 2021年03月27日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Certain non-steroidal anti-inflammatory drugs (NSAIDs) are known to have anticancer effects. However, it is unclear whether all NSAIDs have anticancer effects, and thus far, very few studies have compared the antitumor effects among multiple NSAIDs. Therefore, we aimed to identify NSAIDs that enhance the anticancer effect of cisplatin (CDDP); the effects of 17 NSAIDs in lung cancer cells and their spheroids as cancer stem cells (CSCs) were evaluated. Some of the NSAIDs showed cytotoxic effects against A549 and SBC-3 cells and their CDDP-resistant cell lines (A549/DDP and SBC-3/DDP cells, respectively). In addition, co-addition of CDDP and celecoxib, which showed cytotoxic effects, increased the resistance to CDDP by increasing SLC7A11, which is one of the CDDP resistance mechanisms, in A549/DDP and SBC-3/DDP cells. On the other hand, celecoxib also showed antitumor effects on the spheroids of A549/DDP and SBC-3/DDP cells, and enhanced the antitumor effect of CDDP while increasing the mRNA levels of SLC7A11. Moreover, diclofenac was also cytotoxic and enhanced the cytotoxic effect of CDDP in cancer cells and CSCs. In conclusion, some NSAIDs including celecoxib and diclofenac may enhance the therapeutic efficacy of CDDP.
• Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer.
  Yoshitaka Saito; Yoh Takekuma; Masaki Kobayashi; Naofumi Shinagawa; Yasushi Shimizu; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Ken Iseki; Mitsuru Sugawara
  European journal of clinical pharmacology, 77, 3, 381, 388, 2021年03月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. METHODS: Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. RESULTS: Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively). CONCLUSION: This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.
• Benzodiazepine Concentrations in the Breast milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose.
  Ayako Nishimura; Ayako Furugen; Takeshi Umazume; Seika Kitamura; Mayuko Soma; Kiwamu Noshiro; Yoh Takekuma; Mitsuru Sugawara; Ken Iseki; Masaki Kobayashi
  Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine, 16, 5, 424, 431, 2021年01月15日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Objective:
  Benzodiazepines are common therapies for mental illness and insomnia, and are used during pregnancy and lactation. Although benzodiazepines have been shown to be transferred into breast milk, the amount transferred is small and compatible with breastfeeding. However, information is not available for all drugs. Therefore, we aimed to determine the milk to plasma (M/P) ratio and relative infant dose (RID), which are used as indicators of drug transfer to breast milk, to determine the safety of such drugs for lactating women and breastfeeding infants.
  Methods:
  The study comprised of 11 pregnant women who visited the obstetrics department of Hokkaido University Hospital (approval number: 017-0131) and Tenshi Hospital (approval number: 103) for childbirth. The samples were analyzed using liquid chromatography-tandem mass spectrometry, and the M/P ratio and RID were calculated. The condition of the mother and baby at 1 month after delivery was determined from the clinical information. The target benzodiazepines were alprazolam, brotizolam, clonazepam, clotiazepam, etizolam, ethyl loflazepate, flunitrazepam, and lorazepam.
  Results:
  For all drugs, the M/P ratios were <1 and remained constant over time. For drugs other than ethyl loflazepate, the RID values were <10%, which are considered safe; however, even with ethyl loflazepate, it was only slightly >10%. No abnormalities were found in breastfeeding infants whose mothers were receiving these medications.
  Conclusions:
  The RID results of this study suggest that drug exposure through breast milk is small; thus, maternal drug treatment and breastfeeding are compatible.
• Pharmacological Inhibition of MCT4 Reduces 4-Hydroxytamoxifen Sensitivity by Increasing HIF-1α Protein Expression in ER-Positive MCF-7 Breast Cancer Cells.
  Takanobu Nadai; Katsuya Narumi; Ayako Furugen; Yoshitaka Saito; Ken Iseki; Masaki Kobayashi
  Biological & pharmaceutical bulletin, 44, 9, 1247, 1253, 2021年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, The rate of glycolysis in cancer cells is higher than that of normal cells owing to high energy demands, which results in the production of excess lactate. Monocarboxylate transporters (MCTs), especially MCT1 and MCT4, play a critical role in maintaining an appropriate pH environment through lactate transport, and their high expression is associated with poor prognosis in breast cancer. Thus, we hypothesized that inhibition of MCTs is a promising therapeutic target for adjuvant breast cancer treatment. We investigated the effect of MCT inhibition in combination with 4-hydroxytamoxifen (4-OHT), an active metabolite of tamoxifen, using two estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. Lactate transport was investigated in cellular uptake studies. The cytotoxicity of 4-OHT was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In both cell lines evaluated, MCT1 and MCT4 were constitutively expressed at the mRNA and protein levels. [14C]-L-lactate uptake by both cells was significantly inhibited by bindarit, a selective MCT4 inhibitor, but weakly affected by 5-oxoploline (5-OP), a selective MCT1 inhibitor. The results of the MTT assay showed that combination with bindarit, but not 5-OP, decreased 4-OHT sensitivity. Bindarit significantly increased the levels of hypoxia-inducible factor-1α (HIF-1α) in MCF-7 cells. Moreover, HIF-1α knockdown significantly increased 4-OHT sensitivity, whereas induction of HIF-1α by hypoxia decreased 4-OHT sensitivity in MCF-7 cells. In conclusion, pharmacological MCT4 inhibition confers resistance to 4-OHT rather than sensitivity, by increasing HIF-1α protein levels. In addition, HIF-1α inhibition represents a potential therapeutic strategy for enhancing 4-OHT sensitivity.
• Analysis of α-Defensin 5 Secretion in Differentiated Caco-2 Cells: Comparison of Cell Bank Origin.
  Genki Yasuda; Masaki Kobayashi; Atsuhito Kubota; Katsuya Narumi; Ayako Furugen; Yoshitaka Saito; Takashi Satoh; Natsuko Suzuki; Ken Iseki
  Biological & pharmaceutical bulletin, 44, 2, 275, 278, 2021年, ［査読有り］, ［責任著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, α-Defensin 5 has a particularly broad antibacterial spectrum; it eliminates pathogenic microorganisms and regulates intestinal flora. Although Caco-2 cells are similar to small intestinal cells, it is unclear whether they secrete α-defensin 5. Therefore, we investigated whether Caco-2 cells secrete α-defensin 5 and determined the secretion mechanism using cells from three cell banks (ATCC, DSMZ, and RIKEN). The Caco-2 cell proliferation rate increased with the number of culture days, irrespective of cell bank origin. On the other hand, the alkaline phosphatase activity, which affects cell differentiation and the mRNA levels of several cytokines, such as interleukin 8 (IL-8), IL-6, IL-1β, tumor necrosis factor-α (TNF-α), and IL-2, in the Caco-2 cells fluctuated with the number of culture days, and differed for each cell bank. α-Defensin 5 secretion was detected in all three cell bank Caco-2 cells; particularly, the ATCC Caco-2 cells grew linearly depending on the cell culture day as well as the levels of IL-8 and TNF-α mRNA. This suggested that α-defensin 5 secretion in the ATCC Caco-2 cells was associated with fluctuations in the mRNA levels of various cytokines, such as IL-8 and TNF-α. In conclusion, Caco-2 cells may be a simple model for screening health food components and drugs that affect α-defensin 5 secretion.
• Detection of risk factors related to administration suspension and severe neutropenia in gemcitabine and nab-paclitaxel treatment.
  Yoshitaka Saito; Yoh Takekuma; Masaki Kobayashi; Yoshito Komatsu; Mitsuru Sugawara
  Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 29, 6, 3277, 3285, 2020年10月26日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: The combination of gemcitabine (GEM) and nanoparticle albumin-bound paclitaxel (nab-PTX) is an effective chemotherapeutic regimen for locally advanced and metastatic pancreatic cancer. The dose-limiting toxicities (DLTs) of this treatment are sepsis and neutropenia, while the relative dose intensity (RDI) of GEM is approximately 75% and of nab-PTX is 70-80%. In this study, we evaluated the risk factor(s) regarding treatment suspension, which leads to reduction in the RDI of these agents, enabling appropriate schedule management. METHODS: Two hundred patients with pancreatic cancer who received GEM + nab-PTX were retrospectively investigated. Frequency and risk factor(s) of suspension of the treatment and grade 3/4 neutropenia in the first course were evaluated. RESULTS: The frequency of treatment suspension in the first course was 61%. The frequency of grade 3/4 neutropenia was 51%, while that of thrombocytopenia was 7.5%. The RDI was 78.0% for GEM and 77.7% for nab-PTX. Univariate and multivariate analyses to identify risk or preventive factors related to treatment suspension suggested that low platelet count at baseline was a risk factor, whereas dose reduction from the treatment initiation was a preventive factor. The most common cause of abeyance was grade 3/4 neutropenia (83.6%), the risk factors of which were low platelet count and age ≥ 65 years at baseline, while dose reduction was a preventive factor. CONCLUSION: We found that a low platelet level at baseline was a risk factor, whereas dose reduction from initiation was a preventive factor in regard to treatment suspension and severe neutropenia occurrence in GEM + nab-PTX treatment.
• Identification of the essential extracellular aspartic acids conserved in human monocarboxylate transporters 1, 2, and 4.
  Atsushi Yamaguchi; Katsuya Narumi; Ayako Furugen; Ken Iseki; Masaki Kobayashi
  Biochemical and biophysical research communications, 529, 4, 1061, 1065, 2020年09月03日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human monocarboxylate transporters (hMCTs) 1-4 transport monocarboxylates, such as l-lactate and pyruvate, as well as H+ across the plasma membrane. hMCT1, 2, and 4 play important roles in energy balance, pH homeostasis. However, the molecular mechanism of these transporters, especially their pH dependency, remains unknown. The aim of this study was to identify the residues involved in the pH dependence of hMCT1, 2, and 4. Firstly, we focused on the effects of extracellular acids of hMCT1. l-Lactate uptake assay and site-directed mutagenesis revealed that the aspartic acid of hMCT1 (hMCT1 D414) was an important residue conserved in MCT1, 2, and 4 (hMCT2 D398 and hMCT4 D379). Because the functional characteristic of hMCT2-mediated l-lactate transport has not been reported, we built a hMCT2-expressing system using Xenopus laevis oocytes. The transport activity of hMCT2 was enhanced by co-expression with embigin, an ancillary protein, and kinetic analysis of hMCT2-mediated l-lactate uptake revealed that the apparent Km value (0.32 ± 0.02 mM) was lower than that mediated by hMCT1 and 4. Finally, we investigated the conserved aspartic acids of hMCT2 and 4, and revealed that these residues were essential for l-lactate transport. These findings suggested that the extracellular aspartic acids conserved in hMCT1, 2, and 4 played important roles in transport activity and pH dependency, and can function as a first step of substrate and H+ recognition and transport from the extracellular to the intracellular region. These findings contributed to enhance our understanding of the transport process of hMCT1, 2, and 4.
• Association between N-desmethylclozapine and clozapine-induced sialorrhea: Involvement of increased nocturnal salivary secretion via muscarinic receptors by N-desmethylclozapine.
  Shuhei Ishikawa; Masaki Kobayashi; Naoki Hashimoto; Hideaki Mikami; Akihiko Tanimura; Katsuya Narumi; Ayako Furugen; Ichiro Kusumi; Ken Iseki
  The Journal of pharmacology and experimental therapeutics, 375, 2, 376, 384, 2020年08月29日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment for CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and drooling severity and frequency scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca2+) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells), and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva N-desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, N-desmethylclozapine concentrations in serum and submandibular glands of rats were higher than clozapine concentrations. In our in vitro study, N-desmethylclozapine only elicited an increase in the intracellular Ca2+ in HSY cells. N-desmethylclozapine-induced Ca2+ responses were inhibited by atropine. These results suggest that N-desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. Significance Statement Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction. Although the mechanism underlying CIS is less well understood. This paper reports that N-desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors, and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.
• Different mechanisms of cisplatin resistance development in human lung cancer cells.
  Keisuke Okamoto; Yoshitaka Saito; Katsuya Narumi; Ayako Furugen; Ken Iseki; Masaki Kobayashi
  Biochemical and biophysical research communications, 530, 4, 745, 750, 2020年08月08日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Cisplatin (CDDP) is a highly potent and important anticancer drug in lung cancer treatment. Long-term use of an anticancer agent causes resistance in cancer cells, and CDDP resistance involves multiple mechanisms. As the mechanism of resistance development differs depending on the cancer cell types, we aimed to evaluate the detailed mechanism of resistance to CDDP in two types of lung cancer cells: SBC-3 and A549 cells. The CDDP-resistant SBC-3/DDP and A549/DDP cells were established through continuous treatment with a gradually increasing dose of CDDP. The viability of SBC-3/DDP and A549/DDP cells treated with CDDP was 3.68 and 2.08 times higher than that of the respective parental cells. Moreover, SBC-3/DDP cells showed significantly increased cystine/glutamate transporter (xCT) mRNA level, and A549/DDP cells showed markedly increased sex determining region Y-box 2 (SOX2) mRNA level. Moreover, the uptake of cystine, a substrate of xCT, was higher in SBC-3/DDP cells than in SBC-3 cells, and cystine uptake in A549/DDP cells was not different from that in A549 cells. In addition, co-treatment with CDDP and sulfasalazine, an xCT inhibitor, showed lower the concentration of 50% inhibition for cell viability than CDDP alone in SBC-3 and SBC-3/DDP cells, but not in A549 and A549/DDP cells. Furthermore, SBC-3 cells transiently overexpressing xCT were resistant to CDDP, and xCT knockdown in A549/DDP cells did not significantly change the level of SOX2 mRNA and viability of cells upon CDDP treatment. In conclusion, the two lung cancer cell lines showed different mechanisms of resistance to CDDP.
• Validation of the usefulness of artificial neural networks for risk prediction of adverse drug reactions used for individual patients in clinical practice
  Shungo Imai; Yoh Takekuma; Hitoshi Kashiwagi; Takayuki Miyai; Masaki Kobayashi; Ken Iseki; Mitsuru Sugawara
  PLOS ONE, 15, 7, e0236789, e0236789, Public Library of Science (PLoS), 2020年07月29日, ［査読有り］
  研究論文（学術雑誌）
• Comparison of the nephroprotective effects of non-steroidal anti-inflammatory drugs on cisplatin-induced nephrotoxicity in vitro and in vivo.
  Keisuke Okamoto; Yoshitaka Saito; Katsuya Narumi; Ayako Furugen; Ken Iseki; Masaki Kobayashi
  European journal of pharmacology, 884, 173339, 173339, 2020年07月26日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Cisplatin (CDDP) is an anticancer drug, often used in the treatment of several types of cancers. CDDP-induced nephrotoxicity (CIN) is one of the most severe adverse events associated with the use of CDDP. It has been suggested that the co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) is a risk factor for CIN. However, the specific NSAIDs that affect CIN and the precise mechanisms underlying this interaction remain unclear. Hence, we aimed to evaluate the effect of NSAIDs on CDDP-induced cytotoxicity in vitro and confirmed the results in vivo. Using the epithelioid clone of the normal rat kidney cells (NRK-52E cells), we assessed the effects of 17 NSAIDs on CDDP-induced cytotoxicity all at once using the MTT assay. Furthermore, we evaluated two NSAIDs, which significantly attenuated or enhanced CDDP-induced cytotoxicity, in vivo. Wistar rats were treated with CDDP (5 mg/kg, i.p., day 1) and NSAIDs (p.o., day 1-4), and the kidneys were excised on day 5. Our results demonstrated that several NSAIDs attenuated, while others enhanced CDDP-induced cytotoxicity. Celecoxib significantly attenuated and flurbiprofen markedly enhanced cell dysfunction by CDDP. These results were reproduced in vivo as celecoxib decreased and flurbiprofen increased the expression of kidney injury molecule 1 (Kim-1) mRNA, a sensitive kidney injury marker, compared to the CDDP group. Moreover, celecoxib increased the antioxidant and autophagy markers quantified by qPCR in vitro and prevented a decrease in body weight induced by CDDP in vivo. In conclusion, we revealed that celecoxib significantly attenuated CIN in vitro and in vivo.
• Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats.
  Hinata Ueda; Katsuya Narumi; Yu Sato; Ayako Furugen; Masaki Kobayashi; Ken Iseki
  Pharmacological reports : PR, 72, 5, 1426, 1432, 2020年07月15日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Methotrexate (MTX), an antifolate agent, is primarily eliminated by the kidney. Organic anion transporter 3 (OAT3) contributes to renal MTX clearance. Several studies have shown an association between co-administration of proton pump inhibitors (PPIs) and delayed elimination of MTX, but the findings are conflicting. In this study, we aimed to evaluate whether the differential inhibitory effects of PPIs on the OAT3-mediated transport of MTX are associated with the risks of delayed MTX elimination. METHODS: We investigated the effects of PPIs on rat (r) OAT3-mediated MTX uptake using HEK293T cells expressing rOAT3. To examine whether PPIs could affect the pharmacokinetics of MTX, changes in plasma concentration-time profiles were assessed when MTX (50 mg/kg, ip) and a range of PPIs (2 mg/kg, iv) were administered to rats. RESULTS: In vitro studies demonstrated that PPIs inhibited rOAT3-mediated uptake of MTX, with estimated IC50 values of 2.1-5.2 μM, and a rank order of esomeprazole ≈ lansoprazole ≈ omeprazole > rabeprazole. When MTX and esomeprazole were co-administered to rats, the plasma concentration of MTX 6 h after administration and the t1/2 were significantly higher than those in the vehicle group. The effect of lansoprazole was not significant, but showed a tendency to prolong plasma MTX levels. Famotidine, a histamine H2-receptor antagonist, showed a weak inhibitory effect on rOAT3-mediated MTX uptake, although it did not affect plasma concentration-time profile of MTX in vivo. CONCLUSION: Esomeprazole increases the t1/2 of MTX in rats, which may be partially attributed to the inhibition of rOAT3.
• Effect of palonosetron and dexamethasone administration on the prevention of gastrointestinal symptoms in hepatic arterial chemoembolization with epirubicin.
  Tatsuhiko Sakamoto; Yoshitaka Saito; Masaki Kobayashi; Takehiro Yamada; Yoh Takekuma; Masato Nakai; Koji Ogawa; Ken Iseki; Mitsuru Sugawara
  Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 28, 7, 3251, 3257, 2020年07月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: There are several studies on premedication to prevent postembolization syndromes which occurs after transcatheter arterial chemoembolization (TACE), but the medication to be used is still not established. This study aimed to examine the effect of palonosetron and dexamethasone on the prevention of gastrointestinal symptoms induced by TACE. METHODS: Patients with hepatocellular carcinoma who were treated with TACE with epirubicin were retrospectively evaluated. The complete response rate of antiemetic drugs and incidence and severity of gastrointestinal symptoms were compared between the antiemetic group (AE group), which includes 51 patients prophylactically administered with palonosetron 0.75 mg and dexamethasone 9.9 mg intravenously before TACE on day 1 and dexamethasone 6.6 mg intravenously on days 2 and 3, and control group with 101 patients without antiemetic premedication. RESULTS: Complete response rate in the entire evaluation period was significantly higher in the AE group compared with that in the control group. In the acute phase, the incidence and severity of nausea, vomiting, and anorexia significantly decreased in the AE group, but only anorexia improved in the delay phase. Additionally, postembolization syndromes, such as abdominal pain and fever, were significantly attenuated in the AE group; however, constipation worsened in this group. CONCLUSIONS: Premedication of palonosetron and dexamethasone significantly prevents the incidence and reduces the severity of gastrointestinal symptoms especially in the acute phase. Further studies will be needed to determine the most recommended 5-HT3 antagonist or dosage of dexamethasone in establishing the optimal antiemetic regimen.
• Evaluation of daptomycin-induced cellular membrane injury in skeletal muscle.
  Takehiro Yamada; Shuhei Ishikawa; Nobuhisa Ishiguro; Masaki Kobayashi; Ken Iseki
  Biological & pharmaceutical bulletin, 43, 9, 1338, 1345, 2020年06月23日, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.
• Cellular uptake properties of lamotrigine in human placental cell lines: Investigation of involvement of organic cation transporters (SLC22A1-5).
  Nami Hasegawa; Ayako Furugen; Kanako Ono; Mai Koishikawa; Yuki Miyazawa; Ayako Nishimura; Takeshi Umazume; Katsuya Narumi; Masaki Kobayashi; Ken Iseki
  Drug metabolism and pharmacokinetics, 35, 3, 266, 273, 2020年06月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Lamotrigine (LTG) is an important antiepileptic drug for the treatment of seizures in pregnant women with epilepsy. However, it is not known if the transport of LTG into placental cells occurs via a carrier-mediated pathway. The aim of this study was to investigate the uptake properties of LTG into placental cell lines (BeWo and JEG-3), and to determine the involvement of organic cation transporters (OCTs, SLC22A1-3) and organic cation/carnitine transporter (OCTNs, SLC22A4-5) in the uptake process. The uptake of LTG at 37 °C was higher than that at 4 °C. OCT1 and OCTNs were detected in both cell lines. The uptake of LTG was not greatly affected by the extracellular pH, Na+-free conditions, or the presence of l-carnitine, suggesting that OCTNs were not involved. Although several potent inhibitors of OCTs (chloroquine, imipramine, quinidine, and verapamil) inhibited LTG uptake, other typical inhibitors had no effect. In addition, siRNA targeted to OCT1 had no significant effect on LTG uptake. The mRNA expression in human term placenta followed the order OCTN2 > OCT3 > OCTN1 > OCT1 ≈ OCT2. These observations suggested that LTG uptake into placental cells was carrier-mediated, but that OCTs and OCTNs were not responsible for the placental transport process.
• Effects of single and repetitive valproic acid administration on the gene expression of placental transporters in pregnant rats: An analysis by gestational period.
  Naoko Jinno; Ayako Furugen; Yuko Kurosawa; Yuki Kanno; Katsuya Narumi; Masaki Kobayashi; Ken Iseki
  Reproductive toxicology (Elmsford, N.Y.), 96, 47, 56, 2020年05月11日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The use of valproic acid (VPA), an antiepileptic drug, during pregnancy, is known to increase various fetal risks. Since VPA has been known to inhibit histone deacetylases (HDACs); its administration could alter gene transcription levels. However, in vivo effects of VPA administration on placental transporters have not been fully elucidated. The purpose of the present study was to comprehensively evaluate the effects of single and repetitive VPA administration on the expression of placental transporters and analyze them by gestational day. We investigated 18 transporters (8 ATP-binding cassette (ABC) and 10 solute carrier (SLC) transporters) in the placentas of pregnant rats that were orally administered 400 mg/kg/day VPA for one or four days, during mid- or late gestation. In the control rats, 4 ABC transporter genes (Abcb1a, 1b, Abcc2, Abcc4) were upregulated, 3 (Abcc3, Abcc5, Abcg2) downregulated through gestation, whereas 1 (Abcc1) was not changed. Regarding SLC transporters, 6 genes (Slc7a5, Slc16a3, Slc22a3, Slc22a4, Slco2b1, Slco4a1) were increased, 1 (Slc29a1) decreased through gestation, whereas 3 (Slc7a8, Slc22a5, Slco2a1) showed no significant change. Single VPA administration altered the expression of 9 transporters and repetitive administration, 13 transporters. In particular, VPA remarkably decreased Abcc4 and Slc22a4 in late gestation and increased Abcc5 during mid-gestation. Our findings indicated that VPA administration changed transporter expression levels in rat placenta, and suggested that sensitivity to VPA differs across gestational stages.
• Non-steroidal Anti-inflammatory Drugs Are a Risk Factor for Cisplatin-induced Nephrotoxicity: A Meta-analysis of Retrospective Studies.
  Keisuke Okamoto; Yoshitaka Saito; Katsuya Narumi; Ayako Furugen; Ken Iseki; Masaki Kobayashi
  Anticancer research, 40, 3, 1747, 1751, 2020年03月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Previous reports have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) are a risk factor for cisplatin-induced nephrotoxicity (CIN). Here, the results of these previous studies were comprehensively assessed via a meta-analysis. MATERIALS AND METHODS: After a database search to select eligible studies, a meta-analysis was performed using a forest plot, followed by an assessment of the heterogeneity and publication bias and a subgroup analysis. RESULTS: Seven studies were extracted as candidates. All were retrospective studies and evaluated the effect of NSAIDs on CIN as a secondary endpoint. According to the meta-analysis, total odds ratio was 1.88 (95% confidence interval=1.44-2.45). Further, high heterogeneity and publication bias were not observed. A subgroup analysis of the chemotherapy evaluation period revealed that CIN tended to be enhanced in the first course group (evaluation in only 1 course) and was significantly enhanced in the total course group (evaluation in 1 or more courses) by NSAIDs co-administration. CONCLUSION: NSAIDs co-administration could be a risk factor for CIN.
• Molecular characterization of the orphan transporter SLC16A9, an extracellular pH- and Na+-sensitive creatine transporter.
  Yuya Futagi; Katsuya Narumi; Ayako Furugen; Masaki Kobayashi; Ken Iseki
  Biochemical and biophysical research communications, 522, 2, 539, 544, 2020年02月05日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human monocarboxylate transporters (hMCTs) mediate the transport of monocarboxylates across plasma membranes. One such transporter, hMCT9, has been shown to be related to serum uric acid levels and the risk of renal overload gout. However, the functional characteristics of hMCT9 remain unknown. The aim of this study was to investigate the expression and localization of hMCT9 using a Xenopus laevis oocyte heterologous expression system and characterize its transport properties. Kinetic analysis of hMCT9-mediated creatine uptake revealed that uptake consisted of two components, with apparent Km values of 237 mm (low-affinity) and 23.7 mm (high-affinity), respectively. The transport activity of hMCT9 was dependent on the extracellular pH and activity sharply increased with increasing pH. Under Na+-free conditions, hMCT9-mediated creatine uptake was reduced by one-half, indicating that hMCT9 is a Na+-sensitive transporter. Moreover, carbonyl cyanide 3-chlorophenylhydrazone (a protonophore) inhibited hMCT9 activity, whereas valinomycin (a K+-ionophore) did not inhibit the transporter. These results suggest that hMCT9 is susceptible to changes in H+ gradients. A cis-inhibition assay of hMCT9-and hMCT12-mediated creatine transport revealed that cyclocreatine, creatine, guanidineacetate, and 3-guanidinopropionate are recognized by the transporter, and 4-guanidinobutyrate and guanidinoethyl sulfonate selectively inhibited hMCT9 activity. These findings demonstrate that hMCT9 is an extracellular pH- and Na+-sensitive creatine transporter.
• Relationships between plasma lactate, plasma alanine, genetic variations in lactate transporters and type 2 diabetes in the Japanese population.
  Issei Higuchi; Yuki Kimura; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Hideaki Miyoshi; Akinobu Nakamura; Takehiro Yamada; Tatsuya Atsumi; Ken Iseki
  Drug metabolism and pharmacokinetics, 35, 1, 131, 138, 2020年02月, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, The present study aimed to characterize the relationships between plasma lactate, plasma alanine, monocarboxylate transporter (MCT) polymorphisms, and indices of diabetes in patients with type 2 diabetes (T2D) in Japan. Eighty-three patients with T2D were prospectively enrolled. The gluconeogenesis and glycogenolysis are enhanced and uptake of glucose is decreased in the T2D liver. Since the liver plays an important role in maintaining glucose metabolism, we examined the relationships between liver enzymes and indices of diabetes. Some studies have reported that MCT1 (SLC16A1) polymorphism causes metabolic diseases. In addition, a high frequency of MCT1 polymorphism was reported in a healthy Japanese population. However, little is known about the relationships between T2D and MCT polymorphisms. Plasma l-lactate concentration positively correlated with indices of diabetes (fasting plasma glucose [FPG] and hemoglobin A1c [HbA1c]) and with the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (γ-GTP). MCT1 polymorphisms were associated with all of these markers. We identified no significant correlations between d-lactate or alanine concentrations and any of these markers, but a significant association was observed between l-lactate, a marker of oxidative capacity, and indices of diabetes. We conclude that plasma l-lactate concentration may represent a predictor of the progression or severity of T2D.
• Extracellular lysine 38 plays a crucial role in pH-dependent transport via human monocarboxylate transporter 1.
  Atsushi Yamaguchi; Yuya Futagi; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Biochimica et biophysica acta. Biomembranes, 1862, 2, 183068, 183068, 2020年02月01日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human monocarboxylate transporters (hMCTs) are expressed in many tissues and mediate the transport of various substrates across the plasma membrane. Among hMCTs, hMCT1-4 cotransport H+ with monocarboxylates such as pyruvate and l-lactate, implying that these proteins recognize both substrate and H+. However, the mechanism of translocation, and particularly that of hMCT1 pH-dependent transport, remains largely unknown. This study aimed at identifying residues involved in the pH dependence of hMCT1 using a combination of amino acid-modifying reagents, site-directed mutagenesis in a Xenopus laevis oocyte expression system, and homology modeling. We showed that diethyl pyrocarbonate (DEPC), phenylglyoxal (PGO), and 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt (DIDS), which react with histidine, arginine, and lysine residues respectively, all inhibited hMCT1 activity. Since DEPC, PGO, and DIDS are membrane impermeable reagents, we mutated to other residues individual histidine, arginine, and lysine residues located within the extracellular regions of hMCT1. Analyses of these mutants demonstrated that except for K38, the extracellular basic residues of hMCT1 were not involved in its transport activity and pH dependence. Moreover, analyses of various mutants in which K38 was substituted for another residue and of an hMCT1 homology model focusing on the location of K38 in the three-dimensional structure delineated the mechanism of hMCT1 pH dependence. Collectively, our data indicate that K38 plays an essential role in hMCT1 transport activity. We would like to propose a mechanism whereby K38 is positioned within a hydrophobic and narrow cavity that is part of the transport pathway, and regulates pH-dependent gating of hMCT1.
• Efficacy of additional dexamethasone administration for the attenuation of paclitaxel-associated acute pain syndrome.
  Yoshitaka Saito; Masaki Kobayashi; Takehiro Yamada; Jun Sakakibara-Konishi; Naofumi Shinagawa; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Ken Iseki
  Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 28, 1, 221, 227, 2020年01月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: Paclitaxel-associated acute pain syndrome (P-APS) affects 80% of patients undergoing therapy. Although it has been shown that prednisone administration for 5 days relieves P-APS, detailed results have not been reported thus far. Therefore, in this study, we evaluated the preventive effect of dexamethasone (DEX) administration against P-APS. METHODS: A total of 60 patients who received carboplatin (area under the curve; AUC = 5-6) plus paclitaxel (200 mg/m2) (plus bevacizumab 15 mg/kg, if non-squamous carcinoma of lung) were enrolled. Eight milligrams of DEX was orally administered on days 2 and 3 to the DEX group patients, and the frequency, severity, duration of P-APS, and other adverse effects in the first cycle were retrospectively evaluated and compared to those observed in control group patients, who were not administered DEX on days 2 and 3. RESULTS: No difference in terms of patient characteristics, except for type of cancer, was observed between groups. The results showed that the frequency of all grade P-APS was approximately 70% and there was no difference between groups. Frequency of ≥ G2 P-APS was 40% in the control group and 14% in the DEX group, demonstrating a significant reduction. Duration of P-APS was 5.8 days in the control group and 4.3 days in the DEX group, which tended to become shorter following additional DEX administration, although this was not significant. Adverse effects other than P-APS induced by chemotherapy were similar between the two groups. CONCLUSION: Additional DEX administration is safe and useful for the attenuation of the severity of P-APS.
• Homology modeling and site-directed mutagenesis identify amino acid residues underlying the substrate selection mechanism of human monocarboxylate transporters 1 (hMCT1) and 4 (hMCT4).
  Yuya Futagi; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Cellular and molecular life sciences : CMLS, 76, 24, 4905, 4921, 2019年12月, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human monocarboxylate transporters (hMCTs/SLC16As) mediate the transport of monocarboxylic compounds across plasma membranes. Among the hMCTs, hMCT1 and hMCT4 are expressed in various tissues, and transport substrates involved in energy metabolism. Both transporters mediate L-lactate transport, but, although hMCT1 also transports L-5-oxoproline (L-OPro), this compound is minimally transported by hMCT4. Thus, we were interested in the molecular mechanism responsible for the difference in substrate specificity between hMCT1 and hMCT4. Therefore, we generated 3D structure models of hMCT1 and hMCT4 to identify amino acid residues involved in the substrate specificity of these transporters. We found that the substrate specificity of hMCT1 was regulated by residues involved in turnover number (M69) and substrate affinity (F367), and these residues were responsible for recognizing (directly or indirectly) the -NH- moiety of L-OPro. Furthermore, our homology model of hMCT1 predicted that M69 and F367 participate in hydrophobic interactions with another region of hMCT1, emphasizing its potentially important role in the binding and translocation cycle of L-OPro. Mutagenesis experiments supported this model, showing that efficient L-OPro transport required a hydrophobic, long linear structure at position 69 and a hydrophobic, γ-branched structure at position 367. Our work demonstrated that the amino acid residues, M69 and F367, are key molecular elements for the transport of L-OPro by hMCT1. These two residues may be involved in substrate recognition and/or substrate-induced conformational changes.
• Construction of a flow chart-like risk prediction model of ganciclovir-induced neutropaenia including severity grade: A data mining approach using decision tree.
  Shungo Imai; Takehiro Yamada; Kumiko Kasashi; Nobuhisa Ishiguro; Masaki Kobayashi; Ken Iseki
  Journal of clinical pharmacy and therapeutics, 44, 5, 726, 734, 2019年10月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, WHAT IS KNOWN AND OBJECTIVE: Haematological toxicities such as neutropaenia are a common side effect of ganciclovir (GCV); however, risk factors for GCV-induced neutropaenia have not been well established. Decision tree (DT) analysis is a typical technique of data mining consisting of a flow chart-like framework that shows various outcomes from a series of decisions. By following the flow chart, users can estimate combinations of risk factors that may increase the probability of certain events. In our previous study, we demonstrated the usefulness of this approach in the evaluation of adverse drug reactions. Therefore, we aimed to construct a risk prediction model of GCV-induced neutropaenia including severity grade. METHODS: We performed a retrospective study at the Hokkaido University Hospital and enrolled patients who received GCV between April 2008 and March 2018. Neutropaenia was defined as an absolute neutrophil count (ANC) <1500 cells/mm3 and a decrease to <75% relative to baseline. We classified the patients who developed neutropaenia in three groups (Grades 2-4) based on the National Cancer Institute-Common Terminology Criteria for Adverse Events. Data collection was achieved through the retrieval of medical records. We employed a chi-squared automatic interaction detection algorithm to construct the DT model and compared the accuracies to the logistic regression model (a conventional statistical method) to evaluate the established model. RESULTS AND DISCUSSION: In total, 396 adult patients were included in the study; 61 (15.4%) developed neutropaenia. Three predictive factors (hematopoietic stem cell transplantation, baseline ANC <3854 cells/mm3 and duration of therapy ≥15 days) were extracted using the DT analysis to produce five subgroups, the incidence of neutropaenia ranged between 1.7% and 52.8%. In each subgroup, patients who developed neutropaenia were categorized based on the severity. The accuracies of each model were the same (84.6%), which indicated precision. WHAT IS NEW AND CONCLUSION: We successfully built a risk prediction model of GCV-induced neutropaenia including severity grade. This model is expected to assist decision-making in the clinical setting.
• Black tea extract and theaflavin derivatives affect the pharmacokinetics of rosuvastatin by modulating organic anion transporting polypeptide (OATP) 2B1 activity.
  Ayuko Kondo; Katsuya Narumi; Keisuke Okuhara; Yuka Takahashi; Ayako Furugen; Masaki Kobayashi; Ken Iseki
  Biopharmaceutics & drug disposition, 40, 8, 302, 306, 2019年09月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Theaflavins (TFs) are derived from black tea, an important source of dietary polyphenols. Although the potential interactions between dietary polyphenols and drugs have been demonstrated through in vitro and in vivo studies, little information is available concerning the influence of TFs on drug disposition. Organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in human enterocytes and plays a role in the intestinal absorption of numerous drugs. The current study evaluated the effects of black tea extracts on the pharmacokinetics of rosuvastatin in rats, and investigated the effect of four major TFs (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and theaflavin-3,3'-digallate) on the transport activity of OATP2B1. Black tea extracts significantly decreased the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0 -8 ) of rosuvastatin by 48% and 37%, respectively (p < 0.001 and p < 0.01, respectively). Moreover, OATP2B1-mediated rosuvastatin and estrone-3-sulfate uptake was significantly reduced in the presence of TFs. A kinetic study revealed that the uptake efficiency (in terms of Vmax /Km ) of rosuvastatin was decreased following treatment with TFs. Black tea extracts also reduced OATP2B1-mediated rosuvastatin uptake. These results suggest that black tea reduces the plasma concentrations of rosuvastatin by inhibiting the intestinal OATP2B1-mediated transport of rosuvastatin.
• Quantification of eight benzodiazepines in human breastmilk and plasma by liquid-liquid extraction and liquid-chromatography tandem mass spectrometry: Application to evaluation of alprazolam transfer into breastmilk.
  Ayako Furugen; Ayako Nishimura; Masaki Kobayashi; Takeshi Umazume; Katsuya Narumi; Ken Iseki
  Journal of pharmaceutical and biomedical analysis, 168, 83, 93, 2019年05月10日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Breastfeeding is strongly encouraged for infant and maternal health. Benzodiazepines (BZDs) are widely prescribed drugs for symptoms, such as anxiety and insomnia, which many women could experience during the postpartum period. However, limited information is currently available to evaluate the transfer of different BZDs into breastmilk. In order to assess the proprieties of this medication during breastfeeding, robust and sensitive analytical methods to quantify BZDs are required. For this purpose, we developed a method for quantification of BZDs, including alprazolam, bromazepam, clonazepam, clotiazepam, etizolam, flunitrazepam, lorazepam, and CM7116 (a metabolite of ethyl loflazepate), in human breastmilk and plasma using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Sample preparation was performed by a simple liquid-liquid extraction (LLE) with ethyl acetate. For sample preparation of CM7116, the pretreatment process to completely obtain the metabolite was added before the LLE step. The BZDs were separated by a C18 column using a gradient elution of acetonitrile in aqueous ammonium acetate solution, and were detected in the positive ion electrospray mode with multiple reaction monitoring (MRM). Lower limits of quantification (LLOQs) in breastmilk ranged from 0.25 to 0.5 ng/mL, and those in plasma ranged from 0.5 to 1.0 ng/mL. The intra-day and inter-day precision, and accuracy of data were assessed and found to be acceptable. The developed method was successfully applied to measure the concentration of alprazolam in breastmilk and plasma, which were donated by a lactating woman who had been regularly treated with alprazolam. Milk to plasma (M/P) ratios were calculated as 0.52 (before oral administration) and 0.49 (2 h after administration) 3 days after delivery. The M/P ratio 1 month after delivery was calculated as 0.41 (2 h after administration). We estimated that the relative infant dose (RID) values of alprazolam ranged from 3.11 to 4.61%.
• 下顎埋伏智歯抜歯術におけるセフカペンピボキシルとアモキシシリンの手術部位感染予防効果の比較
  山神 彰; 山田 武宏; 北川 善政; 大廣 洋一; 佐藤 淳; 石黒 信久; 今井 俊吾; 小林 正紀; 井関 健
  医療薬学, 45, 5, 254, 261, (一社)日本医療薬学会, 2019年05月, ［査読有り］
  日本語, 下顎埋伏智歯抜歯術においてセフカペンピボキシル(CFPN-PI)またはアモキシシリン(AMPC)の予防投与を受けた患者の手術部位感染(SSI)発生率を比較した。解析対象となったのはCFPN-PI群129例(男性50例、女性79例、中央値24.0歳)、AMPC群164例(男性75例、女性89例、中央値25.0歳)であった。SSI発生率はCFPN-PI群において11.6%(15/129)、AMPC群において2.4%(4/164)であり、CFPN-PI群のSSI発生率は有意に高かった。次いで、SSI発生に影響する要因分析を行った。単変量解析において抗菌薬(CFPN-PIの使用)、性別(女性)、術後入院、手術難易度、反対側下顎埋伏智歯抜歯の有無、Pell-Gregory分類がP≦0.2となり、これらを多変量解析における解析対象因子として抽出した。解析対象因子のvariance inflation factorはいずれも4未満であり多重共線性はみられなかった。多変量解析の結果、抗菌薬(CFPN-PIの使用)および術後入院がそれぞれオッズ比5.61、4.66を示し、SSIに影響する独立因子として抽出された。
• Construction of a risk prediction model of vancomycin-associated nephrotoxicity to be used at the time of initial therapeutic drug monitoring: A data mining analysis using a decision tree model.
  Shungo Imai; Takehiro Yamada; Kumiko Kasashi; Yusuke Niinuma; Masaki Kobayashi; Ken Iseki
  Journal of evaluation in clinical practice, 25, 1, 163, 170, 2019年02月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVES: In our previous study, we built a risk prediction model of vancomycin (VCM)-associated nephrotoxicity using decision tree (DT) analysis. However, this has several limitations in clinical applications. Our objective here was to construct a clinically applicable risk prediction model to be used at the time of initial therapeutic drug monitoring (TDM), in patients with uncomplicated infections. METHOD: A retrospective study was conducted at Hokkaido University Hospital. Subjects that had received VCM were extracted between November 2011 and April 2017. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dL or 50% or higher from baseline. The additional inclusion criteria in this study were as follows: (1) the target trough level of VCM was set to 10 to 15 mg/L, and (2) the duration of therapy was 7 to 14 days. Patients were assumed to have uncomplicated infections. Risk factors for nephrotoxicity were evaluated, which could be extracted at the initial TDM. In the DT analysis, a chi-squared automatic interaction detection algorithm was constructed. RESULTS: A total of 402 patients were enrolled, and 56 (13.9%) patients developed nephrotoxicity. In the DT analysis, concomitant medications (furosemide, piperacillin-tazobactam, and vasopressor drugs) and an initial VCM trough concentration ≥ 15.0 mg/L were extracted as predictive variables by which patients were divided into six subgroups. The incidence of nephrotoxicity was 5.2% to 70.0%, with subgroups classified as low to high risk of nephrotoxicity. The accuracy of DT model was favourable (87.1%). CONCLUSION: We propose that the DT model built in this study is applicable to clinical practice.
• Mutual role of ecto-5'-nucleotidase/CD73 and concentrative nucleoside transporter 3 in the intestinal uptake of dAMP.
  Katsuya Narumi; Tsukika Ohata; Yuichi Horiuchi; Hiroshi Satoh; Ayako Furugen; Masaki Kobayashi; Ken Iseki
  PloS one, 14, 10, e0223892, 2019年, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 2'-Deoxyadenosine 5'-monophosphate (dAMP), a deoxyribonucleotide found in DNA, affects intestinal cell growth. The molecular mechanisms underlying gastrointestinal absorption of foreign DNA ingested along with food has hardly been investigated. The aim of this study was to investigate the mechanism underlying intestinal absorption of dAMP. The uptake of [3H]dAMP by Caco-2 cells was Na+- and pH-dependent and was inhibited by various nucleosides. In contrast, nitrobenzylthioinosine (NMBPR), an equilibrative nucleoside transporter inhibitor, showed little inhibitory effects on [3H]dAMP uptake. Additionally, human concentrative nucleoside transporter (CNT) 3, transiently expressed in COS-7 cells, mediated the uptake of [3H]dAMP. A kinetic study revealed that the Km value of CNT3-mediated uptake of dAMP (59.6 μM) was close to that of 2'-deoxyadenosine (dAdo) (56.3 μM), whereas the dAMP Vmax (15.6 pmol·mg protein-1min-1) was 500-fold lesser than the dAdo Vmax (7782 pmol·mg protein-1min-1). Further, [3H]dAMP uptake was greater in COS-7 cells expressing ecto-5'-nucleotidase/CD73 with CNT3 than in those expressing CNT3 alone. These data suggest that, although dAMP is a substrate of CNT3, it is dephosphorylated to dAdo by CD73 and is efficiently absorbed as dAdo from the intestinal lumen.
• Analysis of the effects of polyunsaturated fatty acids on transporter expressions using a PCR array: Induction of xCT/SLC7A11 in human placental BeWo cells.
  Kanako Ono; Ayako Furugen; Yuko Kurosawa; Naoko Jinno; Katsuya Narumi; Masaki Kobayashi; Ken Iseki
  Placenta, 75, 34, 41, 2019年01月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVE: Polyunsaturated fatty acids (PUFAs), including arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are essential for adequate fetal growth. The aim of the present study was to elucidate the effects of PUFAs on the expression and function of placental transporters, which play important roles in placental functions including the supply of nutrients to the fetus, excretion of metabolites, and protection of the fetus from xenobiotics. METHODS: Human placental choriocarcinoma BeWo cells were used as a trophoblast model. PUFA-induced alteration in the gene expression of 84 transporters was investigated by a commercially available PCR array. Protein levels and the activity of transporters were assessed by western blotting and uptake experiments, respectively. The placental expression of the transporters was analyzed using pregnant Wistar rats. RESULTS: PUFAs (AA, EPA, and DHA) increased cystine/glutamate transporter xCT/SLC7A11, which mediates the cellular uptake of cystine coupled with the efflux of glutamate in human placental choriocarcinoma BeWo cells. These PUFAs also increased [14C]-cystine uptake in BeWo cells. PUFA-induced xCT/SLC7A11 mRNA expression was not blocked by nuclear factor-erythroid 2-related factor-2 (NRF2) knockdown. Reverse transcription (RT)-PCR analysis indicated that xCT/Slc7a11 mRNA was detected in rat placenta and the expression level at gestational day (GD) 12 was higher than that at GD 20. CONCLUSION: These results indicate that PUFAs promoted cystine uptake in placental cells by inducing xCT/SLC7A11 expression and NRF2 did not contribute to upregulation of xCT/SLC7A11 by PUFAs. Furthermore, xCT expression in rat placenta may change during pregnancy.
• Valproic acid transport in the choriocarcinoma placenta cell line JEG-3 proceeds independently of the proton-dependent transporters MCT1 and MCT4.
  Yuri Ishiguro; Ayako Furugen; Katsuya Narumi; Ayako Nishimura; Takeshi Hirano; Masaki Kobayashi; Ken Iseki
  Drug metabolism and pharmacokinetics, 33, 6, 270, 274, 2018年12月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Medication therapy is the first line of treatment in the management of epilepsy. Fetal exposure to valproic acid (VPA), an antiepileptic drug, poses an elevated risk of teratogenicity in early pregnancy. Some studies have reported that monocarboxylate transporters (MCTs) may be involved in the placental transport of VPA. However, it has not been determined which MCTs contribute to VPA transport into the placenta. Therefore, the aim of this study was to determine how MCTs contribute to VPA transport into the placenta using the human placenta choriocarcinoma cell line JEG-3. VPA uptake was investigated using JEG-3 cells and radiolabeled VPA. MCT expression in JEG-3 cells was detected using RT-PCR and western blotting. Knockdown of MCTs was carried out using siRNAs. VPA uptake into JEG-3 cells was pH- and concentration-dependent, and described by using the Michaelis-Menten equation (Km = 0.95 ± 0.17 mM; Vmax = 19.3 ± 1.21 nmol/mg protein/15 s). MCT1 and MCT4 expression was found in JEG-3 cells, and typical MCT inhibitors significantly inhibited VPA uptake into JEG-3 cells. However, knockdown of MCT1 and MCT4 did not alter VPA uptake. In conclusion, VPA transport is mediated by a proton-dependent transporter in JEG-3 cells, but not by MCT1 and MCT4.
• Valproate sensitizes human glioblastoma cells to 3-bromopyruvate-induced cytotoxicity.
  Yuri Ishiguro; Masaki Kobayashi; Masaya Ideno; Katsuya Narumi; Ayako Furugen; Ken Iseki
  International journal of pharmaceutics, 551, 1-2, 97, 102, 2018年11月15日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Glioblastoma (GBM) is the most common brain tumor; however, no effective treatment for it is available yet. Monocarboxylate transporters, which are highly expressed in GBM, play a role in transporting antitumor agents, such as 3-bromopyruvate (3-BrPA). Valproate, primarily used to treat epilepsy, has been considered a possible treatment option for malignant GBM. In this study, we aimed to investigate the combined effects of 3-BrPA and valproate on GBM cell growth and elucidate the underlying mechanisms. Valproate enhanced 3-BrPA-induced cell death in T98G cells, used as a GBM model. Multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) mRNA levels significantly increased after valproate treatment. 3-BrPA-induced cell death, which was enhanced by valproate, was inhibited in the presence of MK571, a MRP inhibitor, or Ko143, a BCRP inhibitor. In addition, treatment with 3-BrPA and valproate for 48 h reduced cellular ATP levels compared to those in the 3-BrPA alone treatment group. However, cellular ATP levels were recovered in the presence of MK571 or Ko143, compared to those in the 3-BrPA and valproate treatment groups. In conclusion, we suggested that valproate enhanced 3-BrPA-induced cell death. This might be attributable to the increase in cellular ATP consumption owing to valproate-induced MRP2 or BCRP expression.
• 血液培養陽性患者におけるde-escalationの実施状況とその有用性調査
  新沼 悠介; 今井 俊吾; 冨山 直樹; 鏡 圭介; 山神 彰; 山田 武宏; 小林 正紀; 井関 健; 石黒 信久; 福元 達也
  北海道病院薬剤師会誌, 95, 9, 12, (一社)北海道病院薬剤師会, 2018年11月
  日本語, 当院における血液培養陽性患者へのde-escalationの実施状況を調査し、その有用性(薬剤コスト削減効果)を明らかにした。菌種別のde-escalation実施率は、メチシリン感受性黄色ブドウ球菌(MSSA)が最も高く、次いで腸球菌属(Enterococcus spp.)が高かった。抗MRSA薬からの切り替えが最も多く、これはMSSAやEnterococcus spp.のde-escalation実施率の高さに反映されていると考えられた。de-escalation実施群と非実施群における治療失敗率の比較では、両群において有意差は認められなかった。治療失敗例は各群に1例ずつ認められ、その内訳はいずれも培養結果判明後30日以内の死亡であり、感染症の重篤度との関連が疑われた症例である。菌種はそれぞれMSSAとEnterococcus spp.であった。菌の持続的検出・菌血症の再発に関しては両群で認められなかった。治療期間と治療コストの比較については、de-escalation実施群に関して多剤で治療を行っていた症例が有意に多かったため、単剤で治療を行った症例を抽出し比較を行った。治療期間に関しては両群で差は認められなかった。一方、治療コストに関しては実施群で有意に低いという結果となった。
• Genetic variations in the monocarboxylate transporter genes (SLC16A1, SLC16A3, and SLC16A11) in the Japanese population.
  Yuki Kimura; Masaki Kobayashi; Masaru Asari; Issei Higuchi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Drug metabolism and pharmacokinetics, 33, 5, 215, 218, 2018年10月, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, MCT1 (SLC16A1), MCT4 (SLC16A3), and MCT11 (SLC16A11) are members of the monocarboxylate transporter (MCT) family. MCT1 and MCT4 transport pH-related monocarboxylates, such as lactate and pyruvate. MCT11 may also be a proton-coupled monocarboxylate transporter. Although alterations of these substrates are involved in the pathology of cancer and diabetes, little is known about MCT polymorphisms. In this study, genetic variation was evaluated in SLC16A1, SLC16A3, and SLC16A11 in the Japanese population (healthy volunteers, n = 92). Polymorphisms in the coding regions of the SLC16A1, SLC16A3, and SLC16A11 genes were screened by DNA sequencing. A single polymorphism that caused a change in the amino acid sequence was found in SLC16A1 (rs1049434 (T1470A, D490E)) and in SLC16A3 (rs368788465 (C641T, S214F)). Five polymorphisms were detected in the SLC16A11 gene (rs117767867 (G337A, V113I), rs13342692 (A380G, D127G), rs13342232 (T561C, silent), rs75418188 (G1018A, G340S), and rs75493593 (C1327A, P443T)). This information for a healthy population provides a comparison for further studies of patients with various diseases such as cancer and diabetes.
• Evaluation of the effects of antiepileptic drugs on folic acid uptake by human placental choriocarcinoma cells.
  Yuko Kurosawa; Ayako Furugen; Ayako Nishimura; Katsuya Narumi; Masaki Kobayashi; Ken Iseki
  Toxicology in vitro : an international journal published in association with BIBRA, 48, 104, 110, 2018年04月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Folate status during pregnancy is important for fetal development and health. The placenta plays an important role in supplying the fetus with folate. Most women with epilepsy continue their medication during pregnancy. In the present study, we aimed to evaluate the effects of 16 antiepileptic drugs, clinically used for treatment of epilepsy, on folic acid uptake in two in vitro placental models, BeWo and JEG-3 cells. Short-term exposure to antiepileptic drugs had no effects on [3H]-folic acid uptake by BeWo cells. However, long-term exposure (24h) to valproic acid (VPA) increased [3H]-folic acid uptake by BeWo and JEG-3 cells. VPA treatment for 24h increased folate receptor-α (FRα) and proton-coupled folate transporter (PCFT) mRNA expression; however, it did not affect reduced folate carrier expression. These results suggested that the increase in folic acid uptake after exposure to VPA can be attributed to the induction of FRα and PCFT expression. Furthermore, the present study showed that exposure to clinical concentrations of oxcarbazepine and stiripentol reduced the viability of BeWo cells. Therefore, the findings of the present study may contribute to better understanding of the mechanisms of toxicity of antiepileptic drugs, and estimation of their potential risk to fetus.
• Reishi mushroom Ganoderma lucidum Modulates IgA production and alpha-defensin expression in the rat small intestine.
  Atsuhito Kubota; Masaki Kobayashi; Sota Sarashina; Reiko Takeno; Keisuke Okamoto; Katsuya Narumi; Ayako Furugen; Yuji Suzuki; Natsuko Takahashi; Ken Iseki
  Journal of ethnopharmacology, 214, 240, 243, 2018年03月25日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, ETHNOPHARMACOLOGICAL RELEVANCE: Immunoglobulin A (IgA) secretion and alpha-defensins play a role in the innate immune system to protect against infection. Ganoderma lucidum (W.Curt.: Fr.) P. Karst. (Reishi) is a well-known mushroom in traditional Chinese medicine. This study aimed to determine the effects of Reishi on IgA secretion from Peyer's patch (PP) cells and alpha-defensin-5 (RD-5) and RD-6 expression in the rat small intestine. MATERIALS AND METHODS: The rats received an oral injection of 0.5-5mg/kg of Reishi powder (1mL/kg) by sonde. All animals were euthanized 24h after Reishi administration. We examined RD-5, RD-6, and Toll-like receptor (TLR) 4 mRNA levels in the jejunum, ileum, and in Peyer's patches (PP) through quantitative real-time PCR analysis. IgA secretion from PP was measured through enzyme-linked immunosorbent assay of the supernatant after primary culture. RESULTS: Reishi increased IgA secretion in the presence of lipopolysaccharide (LPS) and increased TLR4 mRNA levels, but had no effect on the viability of PP cells. Moreover, Reishi increased RD-5, RD-6, and TLR4 mRNA levels significantly in the ileum in a concentration-dependent manner. CONCLUSIONS: Reishi can induce IgA secretion and increase the mRNA levels of RD-5 and RD-6 in the rat small intestine, through a TLR4-dependent pathway. The present results indicate that Reishi might reduce the risk of intestinal infection.
• Identification of a selective inhibitor of human monocarboxylate transporter 4.
  Yuya Futagi; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Biochemical and biophysical research communications, 495, 1, 427, 432, 2018年01月01日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, The human monocarboxylate transporters (hMCTs/SLC16As) mediate the uptake of various monocarboxylates. Several isoforms of hMCTs are expressed in cancerous tissue as well as in normal tissue. In cancerous tissue, hypoxia induces the expression of hMCT4, which transports the energetic metabolite l-lactate across the plasma membrane. Since hMCT4 is involved in pH regulation and the transport of l-lactate in cancer cells, an hMCT4 inhibitor could function as an anticancer agent. Although several non specific hMCT inhibitors have been developed, a selective hMCT4 inhibitor has not yet been identified. The aim of this study was therefore to identify a selective hMCT4 inhibitor for use as a pharmacological tool for studying hMCT4. The heterologous expression system of the Xenopus oocyte was used to assess the effects of test compounds on hMCT4, whereupon isobutyrate derivatives, fibrates, and bindarit (2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid) were demonstrated to exhibit selective inhibitory effects against this transporter. It is suggested that the structure formed from the joining of an isobutyrate moiety and two aromatic rings by appropriate linkers is important for acquiring the selective hMCT4-inhibiting activity. These findings provide novel insights into the ligand recognition of hMCT4, and contribute to the development of novel anticancer agents.
• Involvement of monocarboxylate transporter 1 (SLC16A1) in the uptake of l-lactate in human astrocytes.
  Masaya Ideno; Masaki Kobayashi; Shotaro Sasaki; Yuya Futagi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Life sciences, 192, 110, 114, 2018年01月01日, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: Astrocytes, the most abundant glial cells in the central nervous system (CNS), help neurons survive. Monocarboxylate transporters (MCTs) are reported to transport l-lactate, which is important for CNS physiology and cognitive function. However, it remains unclear which MCT isoform is functionally expressed by human astrocytes. The aim of this study was to establish the contribution of each MCT isoform to l-lactate transport in human astrocytes. METHODS: The function of l-lactate transport was studied using NHA cells as a human astrocyte model and radiolabeled l-lactate. The expression of MCT in human astrocytes was detected by immunohistochemistry staining. RESULTS: The cellular uptake of l-lactate was found to be pH- and concentration-dependent with a Km value for l-lactate uptake of 0.64mM. This Km was similar to what has been previously established for MCT1-mediated l-lactate uptake. α-Cyano-4- hydroxycinnamate (CHC) and 5-oxoproline, which are both MCT1 inhibitors, were found to significantly inhibit the uptake of l-lactate, suggesting MCT1 is primarily responsible for l-lactate transport. Moreover, MCT1 protein was expressed in human astrocytes. CONCLUSION: pH-dependent l-lactate transport is mediated by MCT1 in human astrocytes.
• Gamma-Aminobutyric Acid (GABA) Attenuates Ischemia Reperfusion-Induced Alterations in Intestinal Immunity.
  Atsuhito Kubota; Masaki Kobayashi; Sota Sarashina; Reiko Takeno; Genki Yasuda; Katsuya Narumi; Ayako Furugen; Natsuko Takahashi-Suzuki; Ken Iseki
  Biological & pharmaceutical bulletin, 41, 12, 1874, 1878, 2018年, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, The aims of this study were to determine the effects of gamma-aminobutyric acid (GABA) on immunoglobulin A (IgA) secretion from Peyer's patch (PP) cells; to assess rat alpha-defensin-5 (RD-5) expression in the rat small intestine; and to determine the effect of GABA on intestinal ischemia reperfusion (I/R) injury-induced intestinal innate immunity. We found that GABA caused an increase in IgA secretion in the presence and absence of lipopolysaccharide (LPS). Moreover, GABA also significantly increased the mRNA levels of RD-5 and superoxide dismutase (Sod) 1, 3. Intestinal I/R was induced by a 30-min occlusion of the superior mesenteric artery followed by a reperfusion for 60-min. This led to a significant decrease in IgA secretion, and mRNA levels of RD-5 and Sod 1-3 in the ileum. On the other hand, administration of GABA before I/R induction had a significant protective effect against oxidative injury and attenuated the effects on intestinal immunity.
• Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug-drug interactions mediated by organic anion transporter 3
  Katsuya Narumi; Yu Sato; Masaki Kobayashi; Ayako Furugen; Kumiko Kasashi; Takehiro Yamada; Takanori Teshima; Ken Iseki
  BIOPHARMACEUTICS & DRUG DISPOSITION, 38, 9, 501, 508, 2017年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Magnesium co-administration decreases cisplatin-induced nephrotoxicity in the multiple cisplatin administration
  Yoshitaka Saito; Keisuke Okamoto; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Takehiro Yamada; Ken Iseki
  LIFE SCIENCES, 189, 18, 22, 2017年11月, ［査読有り］, ［責任著者］
  英語, 研究論文（学術雑誌）
• The flexible cytoplasmic loop 3 contributes to the substrate affinity of human monocarboxylate transporters.
  Yuya Futagi; Shotaro Sasaki; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  Biochimica et biophysica acta. Biomembranes, 1859, 10, 1790, 1795, 2017年10月, ［査読有り］, ［責任著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Human monocarboxylate transporters (hMCTs/SLC16As) mediate the transport of small molecular weight monocarboxylates. Among hMCTs, hMCT1 exhibits high-affinity l-lactate transport and broad substrate recognition, whereas hMCT4 shows highly specific substrate recognition and low-affinity l-lactate transport, indicating that hMCT1 and hMCT4 have different roles in the body. However, the molecular mechanism of transporter-mediated substrate transport remains unknown. The aim of this study is to identify the domain, which determines the substrate selectivity and affinity of hMCT1 and hMCT4. We constructed a chimera, hMCT4/1, in which the cytoplasmic loop 3 (TM6/7loop) region of hMCT4 was replaced by the corresponding region of hMCT1. Xenopus laevis oocyte heterologous expression system was used to characterize functional features of the chimera. We have demonstrated that the substrate affinity of hMCT1 and hMCT4 depends on the TM6/7loop. Non-conserved His237 residue in the TM6/7loop functions as a regulatory moiety of the substrate affinity. In contrast, the substrate selectivity of the transporters did not depend on the TM6/7loop, suggesting that the domain is not directly involved in substrate recognition. Our study provides important insights into the structures and functions of hMCT1 and hMCT4 transporters. These findings contribute to the development of novel hMCT1 and/or hMCT4 inhibitors as anticancer agents.
• Magnesium attenuates cisplatin-induced nephrotoxicity by regulating the expression of renal transporters
  Yoshitaka Saito; Keisuke Okamoto; Masaki Kobayashi; Katsuya Narumi; Takehiro Yamada; Ken Iseki
  EUROPEAN JOURNAL OF PHARMACOLOGY, 811, 191, 198, 2017年09月, ［査読有り］, ［責任著者］
  英語, 研究論文（学術雑誌）
• Insulin stimulates transport of organic anion compounds mediated by organic anion transporting polypeptide 2B1 in the human intestinal cell line Caco-2
  Taku Kobayashi; Takahiro Koizumi; Masaki Kobayashi; Jiro Ogura; Yuichi Horiuchi; Yuki Kimura; Ayuko Kondo; Ayako Furugen; Katsuya Narumi; Natsuko Takahashi; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 32, 2, 157, 163, 2017年04月, ［査読有り］, ［責任著者］
  英語, 研究論文（学術雑誌）
• Organic anion-transporting polypeptide (OATP) 2B1 contributes to the cellular uptake of theaflavin
  Ayuko Kondo; Katsuya Narumi; Jiro Ogura; Ai Sasaki; Keisuke Yabe; Taku Kobayashi; Ayako Furugen; Masaki Kobayashi; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 32, 2, 145, 150, 2017年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation.
  Chihiro Kaneko; Jiro Ogura; Shunichi Sasaki; Keisuke Okamoto; Masaki Kobayashi; Kaori Kuwayama; Katsuya Narumi; Ken Iseki
  Biochimica et biophysica acta. General subjects, 1861, 3, 559, 566, 2017年03月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: A high intake of fructose increases the risk for hyperuricemia. It has been reported that long-term fructose consumption suppressed renal uric acid excretion and increased serum uric acid level. However, the effect of single administration of fructose on excretion of uric acid has not been clarified. METHODS: We used male Wistar rats, which were orally administered fructose (5g/kg). Those rats were used in each experiment at 12h after administration. RESULTS: Single administration of fructose suppressed the function of ileal uric acid excretion and had no effect on the function of renal uric acid excretion. Breast cancer resistance protein (BCRP) predominantly contributes to intestinal excretion of uric acid as an active homodimer. Single administration of fructose decreased BCRP homodimer level in the ileum. Moreover, diphenyleneiodonium (DPI), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), recovered the suppression of the function of ileal uric acid excretion and the Bcrp homodimer level in the ileum of rats that received single administration of fructose. CONCLUSIONS: Single administration of fructose decreases in BCRP homodimer level, resulting in the suppression the function of ileal uric acid excretion. The suppression of the function of ileal uric acid excretion by single administration of fructose is caused by the activation of Nox. The results of our study provide a new insight into the mechanism of fructose-induced hyperuricemia.
• Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity
  Yoshitaka Saito; Masaki Kobayashi; Takehiro Yamada; Kumiko Kasashi; Rio Honma; Satoshi Takeuchi; Yasushi Shimizu; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Ken Iseki
  SUPPORTIVE CARE IN CANCER, 25, 2, 481, 487, 2017年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Involvement of L-type amino acid transporter 1 in the transport of gabapentin into human placental choriocarcinoma cells
  Ayako Furugen; Yuri Ishiguro; Masaki Kobayashi; Katsuya Narumi; Ayako Nishimura; Takeshi Hirano; Ken Iseki
  REPRODUCTIVE TOXICOLOGY, 67, 48, 55, 2017年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Characterization of loxoprofen transport in Caco-2 cells: the involvement of a proton-dependent transport system in the intestinal transport of loxoprofen
  Katsuya Narumi; Masaki Kobayashi; Ayuko Kondo; Ayako Furugen; Takehiro Yamada; Natsuko Takahashi; Ken Iseki
  BIOPHARMACEUTICS & DRUG DISPOSITION, 37, 8, 447, 455, 2016年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Interaction of atorvastatin with the human glial transporter SLC16A1
  Shotaro Sasaki; Yuya Futagi; Masaya Ideno; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  EUROPEAN JOURNAL OF PHARMACOLOGY, 788, 248, 254, 2016年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Effect of diclofenac on SLC16A3/MCT4 by the Caco-2 cell line
  Shotaro Sasaki; Yuya Futagi; Masaya Ideno; Masaki Kobayashi; Katsuya Narumi; Ayako Furugen; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 31, 3, 218, 223, 2016年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity
  Yurika Kikutani; Masaki Kobayashi; Toru Konishi; Shotaro Sasaki; Katsuya Narumi; Ayako Furugen; Natsuko Takahashi; Ken Iseki
  JOURNAL OF PHARMACEUTICAL SCIENCES, 105, 4, 1544, 1549, 2016年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Influence of high glucose state on bromopyruvate-induced cytotoxity by human colon cancer cell lines
  Masaya Ideno; Shotaro Sasaki; Masaki Kobayashi; Yuya Futagi; Katsuya Narumi; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 31, 1, 67, 72, 2016年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Quantification of new antiepileptic drugs by liquid chromatography/electrospray ionization tandem mass spectrometry and its application to cellular uptake experiment using human placental choriocarcinoma BeWo cells
  Ayako Furugen; Masaki Kobayashi; Ayako Nishimura; Shigeo Takamura; Katsuya Narumi; Takehiro Yamada; Ken Iseki
  JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 1002, 228, 233, 2015年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen
  Jiro Ogura; Kaori Kuwayama; Shunichi Sasaki; Chihiro Kaneko; Takahiro Koizumi; Keisuke Yabe; Takashi Tsujimoto; Reiko Takeno; Atsushi Takaya; Masaki Kobayashi; Hiroaki Yamaguchi; Ken Iseki
  BIOCHEMICAL PHARMACOLOGY, 97, 1, 89, 98, 2015年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Pharmacokinetics and the optimal regimen for levofloxacin in critically ill patients receiving continuous hemodiafiltration
  Takeshi Wada; Masaki Kobayashi; Yuichi Ono; Asumi Mizugaki; Kenichi Katabami; Kunihiko Maekawa; Daisuke Miyamoto; Yuichiro Yanagida; Mineji Hayakawa; Atsushi Sawamura; Ken Iseki; Satoshi Gando
  Journal of Intensive Care, 3, 1, 22, BioMed Central Ltd., 2015年05月08日, ［査読有り］
  英語
• Regorafenib Is Transported by the Organic Anion Transporter 1B1 and the Multidrug Resistance Protein 2
  Hiroki Ohya; Yoshihiko Shibayama; Jiro Ogura; Katsuya Narumi; Masaki Kobayashi; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 38, 4, 582, 586, 2015年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Involvement of Histidine Residue His382 in pH Regulation of MCT4 Activity
  Shotaro Sasaki; Masaki Kobayashi; Yuya Futagi; Jiro Ogura; Hiroaki Yamaguchi; Ken Iseki
  PLOS ONE, 10, 4, e0122738, 2015年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Functional Characterization of 5-Oxoproline Transport via SLC16A1/MCT1
  Shotaro Sasaki; Yuya Futagi; Masaki Kobayashi; Jiro Ogura; Ken Iseki
  JOURNAL OF BIOLOGICAL CHEMISTRY, 290, 4, 2303, 2311, 2015年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Quantification of intracellular and extracellular digoxin and ouabain by liquid chromatography/electrospray ionization tandem mass spectrometry
  Hiroaki Yamaguchi; Kazuaki Miyamori; Toshihiro Sato; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Nariyasu Mano; Ken Iseki
  JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 972, 73, 80, 2014年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Quantification of intracellular and extracellular eicosapentaenoic acid-derived 3-series prostanoids by liquid chromatography/electrospray ionization tandem mass spectrometry
  Nobuaki Tanaka; Hiroaki Yamaguchi; Ayako Furugen; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Nariyasu Mano; Ken Iseki
  PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 91, 3, 61, 71, 2014年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Quercetin-3-rhamnoglucoside (rutin) stimulates transport of organic anion compounds mediated by organic anion transporting polypeptide 2B1
  Jiro Ogura; Takahiro Koizumi; Masahiro Segawa; Keisuke Yabe; Kaori Kuwayama; Shunichi Sasaki; Chihiro Kaneko; Takashi Tsujimoto; Masaki Kobayashi; Hiroaki Yamaguchi; Ken Iseki
  BIOPHARMACEUTICS & DRUG DISPOSITION, 35, 3, 173, 182, 2014年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Immunoprotective effect of epigallocatechin-3-gallate on oral anticancer drug-induced α-defensin reduction in Caco-2 cells.
  Takahashi N; Kobayashi M; Ogura J; Yamaguchi H; Satoh T; Watanabe K; Iseki K
  Biological & pharmaceutical bulletin, 37, 3, 490, 492, 2014年03月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Alteration of Pharmacokinetics of Grepafloxacin in Type 2 Diabetic Rats
  Meguho Watanabe; Masaki Kobayashi; Jiro Ogura; Natsuko Takahashi; Hiroaki Yamaguchi; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 17, 1, 25, 33, 2014年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Intestinal P-glycoprotein Expression is Multimodally Regulated by Intestinal Ischemia-Reperfusion
  Yusuke Terada; Jiro Ogura; Takashi Tsujimoto; Kaori Kuwayama; Takahiro Koizumi; Shunichi Sasaki; Hajime Maruyama; Masaki Kobayashi; Hiroaki Yamaguchi; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 17, 2, 266, 276, 2014年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver
  Takashi Tsujimoto; Jiro Ogura; Kaori Kuwayama; Takahiro Koizumi; Shunichi Sasaki; Yusuke Terada; Masaki Kobayashi; Hiroaki Yamaguchi; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 458, 2, 262, 271, 2013年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Megalin Contributes to Kidney Accumulation and Nephrotoxicity of Colistin
  Takahiro Suzuki; Hiroaki Yamaguchi; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Ken Iseki
  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 57, 12, 6319, 6324, 2013年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Intestinal ischemia-reperfusion suppresses biliary excretion of hepatic organic anion transporting polypeptides substrate
  Hajime Maruyama; Jiro Ogura; Asuka Fujikawa; Yusuke Terada; Takashi Tsujimoto; Takahiro Koizumi; Kaori Kuwayama; Masaki Kobayashi; Hiroaki Yamaguchi; Ken Iseki
  Journal of Pharmacy and Pharmaceutical Sciences, 16, 5, 722, 731, 5, 2013年11月17日, ［査読有り］
  英語, 研究論文（学術雑誌）
• Contribution of multidrug resistance-associated proteins (MRPs) to the release of prostanoids from A549 cells
  Ayako Furugen; Hiroaki Yamaguchi; Nobuaki Tanaka; Narumi Shiida; Jiro Ogura; Masaki Kobayashi; Ken Iseki
  PROSTAGLANDINS & OTHER LIPID MEDIATORS, 106, 37, 44, 2013年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Regulation of the Expression and Activity of Glucose and Lactic Acid Metabolism-Related Genes by Protein Kinase C in Skeletal Muscle Cells
  Sho Otake; Masaki Kobayashi; Katsuya Narumi; Shotaro Sasaki; Yurika Kikutani; Ayako Furugen; Meguho Watanabe; Natsuko Takahashi; Jiro Ogura; Hiroaki Yamaguchi; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36, 9, 1435, 1439, 2013年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: Involvement of SREBP-mediated gene regulation
  Masaki Kobayashi; Keisuke Gouda; Ikumi Chisaki; Koji Asada; Jiro Ogura; Natsuko Takahashi; Toru Konishi; Yusuke Koshida; Shotaro Sasaki; Hiroaki Yamaguchi; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 452, 1-2, 36, 41, 2013年08月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Crucial Residue Involved in L-Lactate Recognition by Human Monocarboxylate Transporter 4 (hMCT4)
  Shotaro Sasaki; Masaki Kobayashi; Yuya Futagi; Jiro Ogura; Hiroaki Yamaguchi; Natsuko Takahashi; Ken Iseki
  PLOS ONE, 8, 7, e67690, 2013年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Rapid Stimulating Effect of the Antiarrhythmic Agent Amiodarone on Absorption of Organic Anion Compounds
  Masahiro Segawa; Jiro Ogura; Satoru Seki; Shirou Itagaki; Natsuko Takahashi; Masaki Kobayashi; Takeshi Hirano; Hiroaki Yamaguchi; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 28, 3, 178, 186, 2013年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Quantitative determination of paclitaxel and its metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, in human plasma using column-switching liquid chromatography/tandem mass spectrometry.
  Yamaguchi H; Fujikawa A; Ito H; Tanaka N; Furugen A; Miyamori K; Takahashi N; Ogura J; Kobayashi M; Yamada T; Mano N; Iseki K
  Biomedical chromatography : BMC, 27, 4, 539, 44, 2013年04月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, A column-switching liquid chromatography/electrospray ionization tandem mass spectrometry to determine paclitaxel and its metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, in human plasma was developed. The analytical system had a Shim-Pack MAYI-ODS (10 × 4.6 mm i.d.) trapping column with deproteinization ability that concentrates analytes and removes water-soluble components. This method covered a linearity range of 5-5000 ng/mL of concentrations in plasma for paclitaxel, a range of 0.87-870 ng/mL for 6α-hydroxypaclitaxel and a range of 0.87-435 ng/mL for p-3'-hydroxypaclitaxel. The intra-day precision and inter-day precision of analysis were less than 11.1%, and the accuracy was within ±14.4% at concentrations of 5, 50, 500 and 5000 ng/mL for paclitaxel, 0.87, 8.7, 87 and 870 ng/mL for 6α-hydroxypaclitaxel, and 0.87, 8.7, 87 and 435 ng/mL for p-3'-hydroxypaclitaxel. The total run time was 30 min. Our method was successfully applied to clinical pharmacokinetic investigation.
• Quantification of intact carboplatin in human plasma ultrafitrates using hydrophilic interaction liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study
  Hajime Ito; Hiroaki Yamaguchi; Asuka Fujikawa; Narumi Shiida; Nobuaki Tanaka; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Nariyasu Mano; Ken Iseki
  JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 917, 18, 23, 2013年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Renal uptake of substrates for organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2 is altered in rats with adenine-induced chronic renal failure
  Hiroki Komazawa; Hiroaki Yamaguchi; Kazuhiro Hidaka; Jiro Ogura; Masaki Kobayashi; Ken Iseki
  Journal of Pharmaceutical Sciences, 102, 3, 1086, 1094, John Wiley and Sons Inc., 2013年, ［査読有り］
  英語, 研究論文（学術雑誌）
• A full validated hydrophilic interaction liquid chromatography-tandem mass spectrometric method for the quantification of oxaliplatin in human plasma ultrafiltrates
  Hajime Ito; Hiroaki Yamaguchi; Asuka Fujikawa; Nobuaki Tanaka; Ayako Furugen; Kazuaki Miyamori; Natsuko Takahashi; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Nariyasu Mano; Ken Iseki
  JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 71, 99, 103, 2012年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Regulation of human monocarboxylate transporter 4 in skeletal muscle cells: The role of protein kinase C (PKC)
  Katsuya Narumi; Masaki Kobayashi; Sho Otake; Ayako Furugen; Natsuko Takahashi; Jiro Ogura; Shirou Itagaki; Takeshi Hirano; Hiroaki Yamaguchi; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 428, 1-2, 25, 32, 2012年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Effects of Acidification and Alkalinization Agent on Statins-induced Muscle Toxicity
  Masaki Kobayashi; Kazuhiro Hidaka; Ikumi Chisaki; Natsuko Takahashi; Jiro Ogura; Shirou Itagaki; Takeshi Hirano; Hiroaki Yamaguchi; Ken Iseki
  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 132, 5, 609, 615, 2012年05月, ［査読有り］, ［筆頭著者］
  日本語, 研究論文（学術雑誌）
• A rapid and sensitive LC/ESI-MS/MS method for quantitative analysis of docetaxel in human plasma and its application to a pharmacokinetic study
  Hiroaki Yamaguchi; Asuka Fujikawa; Hajime Ito; Nobuaki Tanak; Ayako Furugen; Kazuaki Miyamori; Natsuko Takahashi; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Nariyasu Mano; Ken Iseki
  JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 893, 157, 161, 2012年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Involvement of Cholesterol Membrane Transporter Niemann-Pick C1-Like 1 in the Intestinal Absorption of Lutein
  Yuki Sato; Risa Suzuki; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Toshihiro Noda; Satoshi Mizuno; Mitsuru Sugawara; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 15, 2, 256, 264, 2012年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Intestinal Ischemia-Reperfusion Increases Efflux for Uric Acid Via Paracellular Route in the Intestine, but Decreases that Via Transcellular Route Mediated by BCRP
  Jiro Ogura; Kaori Kuwayama; Atsushi Takaya; Yusuke Terada; Takashi Tsujimoto; Takahiro Koizumi; Hajime Maruyama; Asuka Fujikawa; Natsuko Takahashi; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Hiroaki Yamaguchi; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 15, 2, 295, 304, 2012年, ［査読有り］
  英語, 研究論文（学術雑誌）
• The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion
  Jiro Ogura; Yusuke Terada; Takashi Tsujimoto; Takahiro Koizumi; Kaori Kuwayama; Hajime Maruyama; Asuka Fujikawa; Atsushi Takaya; Masaki Kobayashi; Shirou Itagaki; Natsuko Takahashi; Takeshi Hirano; Hiroaki Yamaguchi; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 15, 5, 616, 631, 2012年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Quantification of intracellular and extracellular prostanoids stimulated by A23187 by liquid chromatography/electrospray ionization tandem mass spectrometry
  Ayako Furugen; Hiroaki Yamaguchi; Nobuaki Tanaka; Hajime Ito; Kazuaki Miyamori; Asuka Fujikawa; Natsuko Takahashi; Jiro Ogura; Masaki Kobayashi; Takehiro Yamada; Nariyasu Mano; Ken Iseki
  JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 879, 30, 3378, 3385, 2011年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Protective Effect of Soy Isoflavone Genistein on Ischemia-Reperfusion in the Rat Small Intestine
  Yuki Sato; Shirou Itagaki; Setsu Oikawa; Jiro Ogura; Masaki Kobayashi; Takeshi Hirano; Mitsuru Sugawara; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 34, 9, 1448, 1454, 2011年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Protective effect of lutein after ischemia-reperfusion in the small intestine
  Yuki Sato; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Toshihiro Noda; Satoshi Mizuno; Mitsuru Sugawara; Ken Iseki
  FOOD CHEMISTRY, 127, 3, 893, 898, 2011年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Regulation mechanism of ABCA1 expression by statins in hepatocytes
  Masaki Kobayashi; Keisuke Gouda; Ikumi Chisaki; Manami Ochiai; Shirou Itagaki; Ken Iseki
  EUROPEAN JOURNAL OF PHARMACOLOGY, 662, 1-3, 9, 14, 2011年07月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Pharmacokinetic properties of lutein emulsion after oral administration to rats and effect of food intake on plasma concentration of lutein
  Yuki Sato; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Toshihiro Noda; Satoshi Mizuno; Mitsuru Sugawara; Ken Iseki
  BIOPHARMACEUTICS & DRUG DISPOSITION, 32, 3, 151, 158, 2011年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid
  Yuki Sato; Shirou Itagaki; Toshimitsu Kurokawa; Jiro Ogura; Masaki Kobayashi; Takeshi Hirano; Mitsuru Sugawara; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 403, 1-2, 136, 138, 2011年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• AMP-activated protein kinase regulates the expression of monocarboxylate transporter 4 in skeletal muscle
  Ayako Furugen; Masaki Kobayashi; Katsuya Narumi; Meguho Watanabe; Sho Otake; Shirou Itagaki; Ken Iseki
  LIFE SCIENCES, 88, 3-4, 163, 168, 2011年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Regulation of Monocarboxylate Transporter 1 in Skeletal Muscle Cells by Intracellular Signaling Pathways
  Katsuya Narumi; Ayako Furugen; Masaki Kobayashi; Sho Otake; Shirou Itagaki; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 33, 9, 1568, 1573, 2010年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Grapefruit juice enhance the uptake of coenzyme Q10 in the human intestinal cell-line Caco-2
  Shirou Itagaki; Akiko Ochiai; Masaki Kobayashi; Mitsuru Sugawara; Takeshi Hirano; Ken Iseki
  FOOD CHEMISTRY, 120, 2, 552, 555, 2010年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Pharmacokinetics of Oral and Intravenous Administration of Digoxin after Intestinal Ischemia-Reperfusion
  Jiro Ogura; Hajime Maruyama; Masaki Kobayashi; Shirou Itagaki; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 33, 5, 922, 925, 2010年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Protective effects of quercetin-3-rhamnoglucoside (rutin) on ischemia-reperfusion injury in rat small intestine
  Shirou Itagaki; Setsu Oikawa; Jiro Ogura; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  FOOD CHEMISTRY, 118, 2, 426, 429, 2010年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Expression and Role of SNAT3 in the Placenta
  C. Yoshioka; S. Yasuda; F. Kimura; M. Kobayashi; S. Itagaki; T. Hirano; K. Iseki
  PLACENTA, 30, 12, 1071, 1077, 2009年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Liver X receptor regulates expression of MRP2 but not that of MDR1 and BCRP in the liver
  Ikumi Chisaki; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1788, 11, 2396, 2403, 2009年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Response of the ABCG2 promoter in T47D cells and BeWo cells to sex hormone treatment
  Satoru Yasuda; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  MOLECULAR BIOLOGY REPORTS, 36, 7, 1889, 1896, 2009年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells
  Satoru Seki; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1788, 5, 911, 917, 2009年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• In vitro and in vivo antioxidant properties of ferulic acid: A comparative study with other natural oxidation inhibitors
  Shirou Itagaki; Toshirnitsu Kurokawa; Chie Nakata; Yoshitaka Saito; Setsu Oikawa; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  FOOD CHEMISTRY, 114, 2, 466, 471, 2009年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Placental folate transport during pregnancy
  Satoru Yasuda; Satoko Hasui; Chiaki Yamamoto; Chihiro Yoshioka; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 72, 9, 2277, 2284, 2008年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Interaction of coenzyme Q10 with the intestinal drug transporter P-glycoprotein
  Shirou Itagaki; Akiko Ochiai; Masaki Kobayashi; Mitsuru Sugawara; Takeshi Hiran; Ken Iseki
  JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 56, 16, 6923, 6927, 2008年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Amiodarone increases the accumulation of DEA in a human alveolar epithelium-derived cell line
  Satoru Seki; Shirou Itagaki; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31, 7, 1449, 1452, 2008年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Alteration of Mrp2 and P-gp expression, including expression in remote organs, after intestinal ischemia-reperfusion
  Jiro Ogura; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  LIFE SCIENCES, 82, 25-26, 1242, 1248, 2008年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Post-transcriptional regulation of breast cancer resistance protein after intestinal ischemia-reperfusion
  Jiro Ogura; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31, 5, 1032, 1035, 2008年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Association between risk of myopathy and cholesterol-lowering effect: A comparison of all statins
  Masaki Kobayashi; Ikumi Chisaki; Katsuya Narumi; Kazuhiro Hidaka; Toshiki Kagawa; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  LIFE SCIENCES, 82, 17-18, 969, 975, 2008年04月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• A new method for determination of both thalidomide enantiomers using HPLC systems
  Kaname Sgmbongi; Masanori Tanaka; Kelsuke Sakurada; Masakl Kobayasfi; Shlrou Itagaki; Takeshi Hirano; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31, 3, 497, 500, 2008年03月, ［査読有り］
  英語, 研究論文（学術雑誌）
• The inhibitory effects of fluoroquinolones on L-carnitine transport in placental cell line BeWo
  Takeshi Hirano; Satoru Yasuda; Yuki Osaka; Masaru Asari; Masaki Kobayashi; Shirou Itagaki; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 351, 1-2, 113, 118, 2008年03月, ［査読有り］
  英語, 研究論文（学術雑誌）
• The mechanism of carrier-mediated transport of folates in BeWo cells: The involvement of heme carrier protein 1 in placental folate transport
  Satoru Yasuda; Satoko Hasui; Masaki Kobayashi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 72, 2, 329, 334, 2008年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Functional characterization of human monocarboxylate transporter 9 (SLC16A9)
  Kobayashi Masaki; Kagawa Toshiki; Narumi Katsuya; Hidaka Kazuhiro; Itagaki Shirou; Hirano Takeshi; Iseki Ken
  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 128, 47, 48, 2008年, ［査読有り］
• Functional analysis of phenolsulfonphthalein transport system in Long-Evans Cinnamon rats.
  Itagaki S; Chiba M; Kobayashi M; Sugawara M; Kobayashi M; Hirano T; Iseki K
  Biochimica et biophysica acta, 1778, 1, 270, 275, 2008年01月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long-Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in rat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long-Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level.
• Contribution of multidrug resistance-associated protein 2 to secretory intestinal transport of organic anions
  Shirou Itagaki; Makoto Chiba; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31, 1, 146, 148, 2008年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Bicarbonate supplementation as a preventive way in statins-induced muscle damage
  Masaki Kobayashi; Toshiki Kagawa; Katsuya Narumi; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 11, 1, 1, 8, 2008年, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Preventive effects of bicarbonate on cerivastatin-induced apoptosis
  Masaki Kobayashi; Fumie Kaido; Toshiki Kagawa; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 341, 1-2, 181, 188, 2007年08月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Effect of medium pH on the cytotoxicity of hydrophilic statins
  Masaki Kobayashi; Toshiki Kagawa; Rumi Takano; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 10, 3, 332, 339, 2007年05月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Improvement in intestinal coenzyme q10 absorption by food intake
  Akiko Ochiai; Shirou Itagaki; Toshimitsu Kurokawa; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 127, 8, 1251, 1254, 2007年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Efflux transport of n-monodesethylamiodarone by the human intestinal cell-line caco-2 cells
  Emi Kimoto; Satoru Seki; Shirou Itagaki; Maya Matsuura; Masaki Kobayashi; Takeshi Hirano; Yoshikazu Goto; Koji Tadano; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 22, 4, 307, 312, 2007年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Characterization of hepatobiliary organic anion transporters in Long-Evans Cinnamon rats
  Makoto Chiba; Shirou Itagaki; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 22, 5, 387, 390, 2007年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Down-regulation of intestinal multidrug resistance-associated protein 2 in long-evans Cinnamon rats
  Makoto Chiba; Shirou Itagaki; Masaki Kobayashi; Takeshi Hirano; Ken Iseki
  DRUG METABOLISM AND PHARMACOKINETICS, 22, 6, 450, 455, 2007年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells.
  Hirano T; Yasuda S; Osaka Y; Kobayashi M; Itagaki S; Iseki K
  Biochimica et biophysica acta, 1758, 11, 1743, 1750, 2006年11月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that L-carnitine exists as a zwitterion and that member of the OCTN family play an important role in its transport. The aims of this study were to characterize L-carnitine transport in the intestine by using Caco-2 cells and to elucidate the effects of levofloxacin (LVFX) and grepafloxacin (GPFX), which are zwitterionic drugs, on L-carnitine uptake. Kinetic analysis showed that the half-saturation Na+ concentration, Hill coefficient and Km value of L-carnitine uptake in Caco-2 cells were 10.3 +/- 4.5 mM, 1.09 and 8.0 +/- 1.0 microM, respectively, suggesting that OCTN2 mainly transports L-carnitine. LVFX and GPFX have two pKa values and the existence ratio of their zwitterionic forms is higher under a neutral condition than under an acidic condition. Experiments on the inhibitory effect of LVFX and GPFX on L-carnitine uptake showed that LVFX and GPFX inhibited L-carnitine uptake more strongly at pH 7.4 than at pH 5.5. It was concluded that the zwitterionic form of drugs plays an important role in inhibition of OCTN2 function.
• Inhibitory effects of statins on human monocarboxylate transporter 4
  Masaki Kobayashi; Yukio Otsuka; Shirou Itagaki; Takeshi Hirano; Ken Iseki
  INTERNATIONAL JOURNAL OF PHARMACEUTICS, 317, 1, 19, 25, 2006年07月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane
  Y Saito; S Itagaki; S Kubo; M Kobayashi; T Hirano; K Iseki
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 340, 3, 879, 886, 2006年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Transepithelial transport of telmisartan in Caco-2 monolayers
  Y Goto; S Itagaki; S Umeda; M Kobayashi; T Hirano; K Iseki; K Tadano
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 28, 12, 2235, 2239, 2005年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Nateglinide uptake by a ceftibuten transporter in the rat kidney brush-border membrane.
  Kobayashi M; Saito Y; Itagaki S; Hirano T; Iseki K
  Biochimica et biophysica acta, 1715, 1, 19, 24, 2005年08月, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, Nateglinide, a novel oral hypoglycemic agent, possesses a carbonyl group and a peptide-type bond in its structure. We previously reported that nateglinide transport occurs via a single system that may be identical to the ceftibuten/H(+) cotransport system by the rat small intestine. We speculated that the absorption system present on the intestinal epithelium may be similar to that found on the renal tubular epithelium. The aim of this study was to characterize the transporters on the apical side of the kidney that may contribute to the reabsorption of ceftibuten and nateglinide. The uptake of nateglinide by rat renal brush-border membranes is associated with an H(+)-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. In contrast, Gly-Sar, cephradine and cephalexin had no effect on nateglinide uptake. Nateglinide competitively inhibited H(+)-driven transporter-mediated ceftibuten uptake. We conclude that nateglinide transport occurs via a single system that is H(+)-dependent and may be identical to the ceftibuten/H(+) cotransport system.
• Transport mechanism for L-lactic acid in human myocytes using human prototypic embryonal rhabdomyosarcoma cell line (RD cells)
  M Kobayashi; Fujita, I; S Itagaki; T Hirano; K Iseki
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 28, 7, 1197, 1201, 2005年07月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Substrate specificity of the nateglinide/H+ cotransport system for phenolic acids
  Y Saito; S Itagaki; Y Otsuka; Y Kobayashi; H Okumura; M Kobayashi; T Hirano; K Iseki
  JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 53, 15, 6100, 6104, 2005年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Food-drug interaction between ferulic acid and nateglinide involving the fluorescein/H+ cotransport system
  S Itagaki; Y Kobayashi; Y Otsuka; S Kubo; M Kobayashi; T Hirano; K Iseki
  JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 53, 7, 2499, 2502, 2005年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Intestinal uptake of nateglinide by an intestinal fluorescein transporter.
  Itagaki S; Otsuka Y; Kubo S; Okumura H; Saito Y; Kobayashi M; Hirano T; Iseki K
  Biochimica et biophysica acta, 1668, 2, 190, 194, 2005年03月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Nateglinide, a novel oral hypoglycemic agent, rapidly reaches its maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the intestine. However, nateglinide itself is not transported by MCT1 or PEPT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. It has been reported that the uptake of fluorescein by Caco-2 cells occurs via an H+-driven transporter and that the intestinal fluorescein transporter is probably not MCT1. We examined the contribution of the fluorescein transporter to the uptake of nateglinide by Caco-2 cells. Fluorescein competitively inhibited H+-dependent nateglinide uptake. All of fluorescein transporter inhibitors examined reduced the uptake of nateglinide. Furthermore, nateglinide inhibited fluorescein uptake. We conclude that the intestinal nateglinide/H+ cotransport system is identical to the intestinal fluorescein/H+ cotransport system.
• H+-dependent transport mechanism of nateglinide in the brush-border membrane of the rat intestine
  S Itagaki; Y Saito; S Kubo; Y Otsuka; Y Yamamoto; M Kobayashi; T Hirano; K Iseki
  JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 312, 1, 77, 82, 2005年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Mechanism of L-lactic acid transport in L6 skeletal muscle cells.
  Kobayashi M; Itagaki S; Hirano T; Iseki K
  Drug metabolism and pharmacokinetics, 19, 5, 363, 368, 2004年10月, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, L-lactic acid transport plays an important role in the regulation of L-lactic acid circulation into and out of muscle. To clarify the transport mechanism of L-lactic acid in skeletal muscle, L-lactic acid uptake was investigated using a L6 cell line. mRNAs of monocarboxylate transporter (MCT) 1, 2 and 4 were found to be expressed in L6 cells. The [(14)C] L-lactic acid uptake by L6 cells increased up to pH of 6.0. The [(14)C] L-lactic acid uptake at pH 6.0 was concentration-dependent with a K(m) of 3.7 mM. This process was reduced by alpha-cyano-4-hydroxycinnamate, a typical MCT1, 2 and 4 inhibitor. These results suggest that an MCT participates in the uptake of L-lactic acid by L6 cells. [(14)C] L-lactic acid uptake was markedly inhibited by monocarboxylic acids and monocarboxylate drugs but not by dicarboxylic acids and amino acids. Moreover, benzoic acid, a substrate for MCT1, competitively inhibited this process with K(i) of 1.7 mM. [(14)C] L-lactic acid efflux in L6 cells was inhibited by alpha-cyano-4-hydroxycinnamate but not by benzoic acid. These results suggest that [(14)C] L-lactic acid efflux in L6 cells is mediated by MCT other than MCT1.

• ロスバスタチン併用投与は血液胎盤関門上のOATP2B1の輸送機能を修飾し,レミマゾラムの胎盤移行率を変化させる
  佐藤慧; 茶木友浩; 平畑知輝; 鳴海克哉; 小林正紀; 山蔭道明, 日本麻酔科学会学術集会(Web), 72nd, 2025年
• 肝細胞がんの治療抵抗性の克服に向けたモノカルボン酸輸送担体を標的とする新規治療戦略
  向井悠斗; 山口敦史; 菅沼雄大; 松本憲之; 岡本敬介; 古堅彩子; 鳴海克哉; 小林正紀, 日本薬学会年会要旨集(Web), 145th, 2025年
• オレキシン受容体拮抗薬のUPLC/MS/MS定量法構築とヒト乳汁移行性評価への応用
  石川 陽菜; 古堅 彩子; 西村 あや子; 馬詰 武; 青柳 亮一; 石川 修平; 鳴海 克哉; 岡本 敬介; 武隈 洋; 菅原 満; 小林 正紀, TDM研究, 41, 2, 149, 149, 2024年07月
  (一社)日本TDM学会, 日本語
• 記憶形成に関与するhMCT2の機能解明と選択性の高い阻害剤の探索
  山口敦史; 向井悠斗; 佐久間智也; 岡本敬介; 古堅彩子; 鳴海克哉; 小林正紀, 日本薬学会年会要旨集(Web), 144th, 2024年
• AOX1遺伝子の5’上流および3’非翻訳領域におけるSNP解析
  林愛; 鳴海克哉; 上田一奈太; 岡本敬介; 古堅彩子; 小林正紀, TDM研究, 41, 2, 2024年
• 治療抵抗性統合失調症治療薬クロザピンおよび活性代謝物の血中濃度と副作用の関連性
  石川修平; 橋本直樹; 鳴海克哉; 小林正紀; 久住一郎, TDM研究, 41, 2, 2024年
• 薬剤師のための消化管の知識 No.6 Helicobacter pylori除菌治療における服薬アドヒアランスへのアプローチとコミュニケーション
  森綾子; 小林正紀, Helicobacter Research, 28, 1, 2024年
• マグネシウムの投与量とシスプラチン起因性腎障害予防効果との関連:メタ回帰分析での検証
  岡本敬介; 齋藤佳敬; 山口敦史; 山口敦史; 鳴海克哉; 小林正紀, 日本薬剤学会年会講演要旨集(CD-ROM), 39th, 2024年
• 下顎埋伏智歯抜歯手術における手術部位感染予測モデルの開発:リサンプリング手法を用いた予後予測モデル
  山神彰; 鳴海克也; 鳴海克也; 齋藤佳敬; 古堅彩子; 今井俊吾; 北川善政; 大廣洋一; 高木諒; 武隈洋; 菅原満; 菅原満; 小林正紀; 小林正紀, 日本医療薬学会年会講演要旨集(Web), 33rd, 2023年
• 分化誘導されたヒト神経芽細胞腫SH-SY5Y細胞における乳酸輸送担体の同定
  佐久間智也; 向井悠斗; 山口敦史; 山口敦史; 石川修平; 古堅彩子; 鳴海克哉; 小林正紀, 日本薬学会年会要旨集(Web), 143rd, 2023年
• アザチオプリン誘発性血液障害および肝障害発現におけるAldehyde oxidase阻害薬剤の影響
  上田一奈太; 鳴海克哉; 古堅彩子; 小林正紀, 日本薬学会年会要旨集(Web), 143rd, 2023年
• メトトレキサート誘発性肝障害におけるアルデヒドオキシダーゼの寄与-基礎および薬剤疫学的アプローチによる検証-
  鳴海克哉; 森山綾子; 上田一奈太; 淺野秀峰; 古堅彩子; 小林正紀, 医療薬学フォーラム講演要旨集, 31st, 2023年
• 長時間作用型ベンゾジアゼピン(BZD)系薬のMilk/Plasma ratio(M/P比)およびRelative Infant Dose(RID)の算出
  西村あや子; 古堅彩子; 馬詰武; 北村聖花; 武隈洋; 菅原満; 菅原満; 小林正紀, 医療薬学フォーラム講演要旨集, 31st, 2023年
• 乳汁・血漿中lacosamideのUPLC/MS/MS定量法ならびに乳汁移行性評価への応用
  古堅彩子; 西村あや子; 馬詰武; 石川陽菜; 鳴海克哉; 小林正紀, 医療薬学フォーラム講演要旨集, 31st, 2023年
• 腹膜透析中に発症した焦点性てんかんに対してラコサミドを導入した小児例の経験
  植田 佑樹; 佐藤 泰征; 林 麻子; 上田 泰弘; 木村 修平; 後藤 健; 中久保 佐千子; 中島 翠; 江川 潔; 岡本 孝之; 白石 秀明; 古堅 彩子; 小林 正紀; 真部 淳, てんかん研究, 40, 2, 467, 467, 2022年08月
  (一社)日本てんかん学会, 日本語
• 酸素環境によるエネルギー代謝変動とMCTs発現および薬物感受性に関する研究
  山口敦史; 山口敦史; 山田勇磨; 向井悠斗; 佐久間智也; 鳴海克哉; 古堅彩子; 小林正紀, 日本薬学会年会要旨集(Web), 142nd, 2022年
• 歯科領域における経口第3世代セフェム系抗菌薬減少戦略の評価:中断時系列分析
  山神彰; 鳴海克哉; 齋藤佳敬; 古堅彩子; 今井俊吾; 北川善政; 大廣洋一; 高木諒; 武隈洋; 菅原満; 菅原満; 小林正紀; 小林正紀, 医療薬学フォーラム講演要旨集, 30th, 2022年
• 胎盤Trophoblastの分化・ホルモン分泌機能に着目した薬剤の影響評価
  大山七海; 古堅彩子; 澤田理子; 西村あや子; 鳴海克哉; 小林正紀, 日本医療薬学会年会講演要旨集(Web), 32, 2022年
• 薬剤師のための消化管の知識 No.2 薬剤師が知っておくべきプロトンポンプ阻害薬による薬物間相互作用リスクとそのメカニズム
  鳴海克哉; 小林正紀, Helicobacter Research, 26, 1, 2022年
• MCT阻害剤がタモキシフェン細胞増殖抑制効果へ及ぼす影響
  灘井 崇宜; 鳴海 克哉; 古堅 彩子; 井関 健; 小林 正紀, 日本薬学会年会要旨集, 141年会, 27V11, pm08S, 2021年03月
  (公社)日本薬学会, 日本語
• hMCT1、2、4の細胞外アスパラギン酸の機能解析
  山口 敦史; 鳴海 克哉; 古堅 彩子; 井関 健; 小林 正紀, 日本薬学会年会要旨集, 141年会, 28V11, pm19, 2021年03月
  (公社)日本薬学会, 日本語
• オンライン会議システムを活用した医療面接実習の実践
  森 綾子; 加藤 いづみ; 柏木 仁; 今井 俊吾; 鳴海 克哉; 佐藤 夕紀; 古堅 彩子; 山田 勇磨; 小林 正紀, 日本薬学会年会要旨集, 141年会, 29V11, pm04, 2021年03月
  (公社)日本薬学会, 日本語
• クロザピン誘発性流涎症のリスク因子の同定と発現メカニズムの解明
  石川修平; 小林正紀; 橋本直樹; 久住一郎, 第14回次世代を担う若手医療薬科学シンポジウム, 2020年11月
• シスプラチンの抗腫瘍効果を増強させるNSAIDsの探索とシスプラチン起因性腎障害との関連
  岡本 敬介; 小林 正紀; 齋藤 佳敬; 古堅 彩子; 鳴海 克哉; 井関 健, 日本薬学会年会要旨集, 140年会, 27Y, am07S, 2020年03月
  (公社)日本薬学会, 日本語
• 下顎埋伏智歯抜歯術におけるセフカペンピボキシルとアモキシシリンの手術部位感染予防効果の比較
  山神 彰; 小林 正紀; 山田 武宏; 北川 善政; 大廣 洋一; 佐藤 淳; 石黒 信久; 今井 俊吾; 武隈 洋; 菅原 満; 井関 健, 日本薬学会年会要旨集, 140年会, 28Z, am10S, 2020年03月
  (公社)日本薬学会, 日本語
• リバース・トランスレーショナルリサーチに基づいたシスプラチン起因性腎障害に 及ぼすNSAIDsの影響の解析
  岡本敬介; 齋藤佳敬; 小林正紀; 古堅彩子; 鳴海克哉; 井関健, 第29回日本医療薬学会年会講演要旨集, 2019年11月
• データマイニング手法を用いた副作用発現リスクの定量的評価モデルの開発 ガンシンクロビル誘発性血小板減少症発現割合の推定モデルの構築
  今井 俊吾; 山田 武宏; 笠師 久美子; 小林 正紀; 井関 健, 日本医薬品情報学会総会・学術大会講演要旨集, 22回, 83, 83, 2019年06月
  (一社)日本医薬品情報学会, 日本語
• 下顎埋伏智歯抜歯術におけるセフカペンピボキシルとアモキシシリンの手術部位感染予防効果の比較
  山神 彰; 山田 武宏; 北川 善政; 大廣 洋一; 佐藤 淳; 石黒 信久; 今井 俊吾; 小林 正紀; 井関 健, 医療薬学, 45, 5, 254, 261, 2019年05月
  下顎埋伏智歯抜歯術においてセフカペンピボキシル(CFPN-PI)またはアモキシシリン(AMPC)の予防投与を受けた患者の手術部位感染(SSI)発生率を比較した。解析対象となったのはCFPN-PI群129例(男性50例、女性79例、中央値24.0歳)、AMPC群164例(男性75例、女性89例、中央値25.0歳)であった。SSI発生率はCFPN-PI群において11.6%(15/129)、AMPC群において2.4%(4/164)であり、CFPN-PI群のSSI発生率は有意に高かった。次いで、SSI発生に影響する要因分析を行った。単変量解析において抗菌薬(CFPN-PIの使用)、性別(女性)、術後入院、手術難易度、反対側下顎埋伏智歯抜歯の有無、Pell-Gregory分類がP≦0.2となり、これらを多変量解析における解析対象因子として抽出した。解析対象因子のvariance inflation factorはいずれも4未満であり多重共線性はみられなかった。多変量解析の結果、抗菌薬(CFPN-PIの使用)および術後入院がそれぞれオッズ比5.61、4.66を示し、SSIに影響する独立因子として抽出された。, (一社)日本医療薬学会, 日本語
• ガンシクロビル誘発性血小板減少症の要因分析とDecision tree解析を用いたリスク推定モデルの構築
  今井 俊吾; 山田 武宏; 笠師 久美子; 小林 正紀; 井関 健, 医薬品情報学, 21, 1, 9, 19, 2019年05月
  ガンシクロビル(GCV)による血小板減少症の発現因子を従来の手法であるロジスティック回帰分析を用いて探索した。さらに、2種の決定木(DT)分析アルゴリズムを用いて血小板減少症発現割合の推定モデルを構築し、そのモデルの妥当性について検討した。GCVの点滴静注製剤の投与を受けた患者386例を対象とした。血小板減少症の発現は12.2%(386例中47例)に認められ、多変量解析において白血球数7000cells/mm3未満、血小板数101000cells/mm3未満、総ビリルビン値0.8mg/dL以上が血小板減少症発現に影響する独立因子として抽出された。CHAID法で構築したDTモデルでは、ツリーは3段階、六つのサブグループに分枝し、五つのリスク因子が抽出された。また、CRT法で構築したモデルでは、ツリーは3段階、七つのサブグループに分枝し、五つのリスク因子が抽出された。ロジスティック回帰モデルならびにCHAID法で構築されたDTモデルの精度は87.8%、CRT法で構築されたDTモデルの精度は88.3%であった。, (一社)日本医薬品情報学会, 日本語
• 病院・薬局薬剤師を対象としたターミナルケア態度尺度(FATCOD-Form B-J)を用いた意識調査
  熊井 正貴; 加藤 信太郎; 小柳 遼; 久保田 康生; 古堅 彩子; 鳴海 克哉; 小林 正紀; 笠師 久美子; 土居 由有子; 郡 修徳; 井関 健, 日本緩和医療薬学雑誌 = Japanese journal of pharmaceutical palliative care and sciences, 12, 1, 1, 8, 2019年03月
  日本緩和医療薬学会, 日本語
• 第2回領域別専門薬剤師によるclinical questionの解決手段と、薬物療法のエビデンス創出に向けて マグネシウム投与によるシスプラチン起因性腎障害の予防効果およびその機序の解明
  齋藤 佳敬; 小林 正紀; 岡本 敬介; 秋田 弘俊; 井関 健, 日本薬学会年会要旨集, 139年会, 1, 260, 260, 2019年03月
  (公社)日本薬学会, 日本語
• 薬学実務実習前後における薬学生のコミュニケーション分析 RIAS(Roter method of interaction process analysis)を用いて
  武隈 洋; 森 綾子; 小林 正紀; 山田 勇磨; 佐藤 夕紀; 鳴海 克哉; 古堅 彩子; 菅原 満, 日本薬学会年会要旨集, 139年会, 4, 212, 212, 2019年03月
  (公社)日本薬学会, 日本語
• EFFECTS OF POLYUNSATURATED FATTY ACIDS ON THE EXPRESSION OF TRANSPORTERS IN HUMAN PLACENTAL CHORIOCARCINOMA CELLS
  Kanako Ono; Ayako Furugen; Yuko Kurosawa; Naoko Jinno; Katsuya Narumi; Masaki Kobayashi; Ken Iseki, PLACENTA, 69, E87, E87, 2018年09月
  英語, 研究発表ペーパー・要旨（国際会議）
• 後方視的臨床研究及びin vivoにおけるマグネシウムのシスプラチン起因性腎障害軽減効果の検証
  岡本敬介; 齋藤佳敬; 小林正紀; 井関健, 第12回次世代を担う若手医療薬科学シンポジウム要旨集, 2018年09月
  研究発表ペーパー・要旨（全国大会，その他学術会議）
• 乳汁および血漿中におけるbenzodiazepine系薬剤のLC/MS/MS定量法の構築
  古堅彩子; 西村あや子; 小林正紀; 馬詰武; 井関健, 医療薬学フォーラム講演要旨集, 26th, 285, 2018年06月
  日本語
• GABA はラット小腸 I/R による腸管免疫変動を抑制する
  窪田 篤人; 小林 正紀; 更科 壮太; 保田 元気; 鳴海 克哉; 古堅 彩子; 鈴木 夏子; 井関 健, 第145回 日本薬学会北海道支部例会, 2018年05月
• NSAIDsのCOX選択性がシスプラチン起因性細胞傷害に及ぼす影響
  岡本敬介; 齋藤佳敬; 古堅彩子; 鳴海克哉; 小林正紀; 井関健; 井関健, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.27C‐am10S, 2018年
  日本語
• 胎盤細胞への葉酸輸送に及ぼす抗てんかん薬の影響の評価
  黒澤優子; 古堅彩子; 西村あや子; 鳴海克哉; 小林正紀; 井関健; 井関健, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.27T‐am10S, 2018年
  日本語
• 2型糖尿病病態とMCT11遺伝子多型との関連性
  木村有希; 樋口一世; 樋口一世; 小林正紀; 小林正紀; 鳴海克哉; 古堅彩子; 三好秀明; 中村昭伸; 渥美達也; 井関健; 井関健, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.27X‐pm02, 2018年
  日本語
• hMCT1,4の基質選択性に関わるアミノ酸残基の探索
  二木悠哉; 二木悠哉; 古堅彩子; 鳴海克哉; 小林正紀; 井関健; 井関健, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.27U‐am06S, 2018年
  日本語
• リネゾリド投与患者における嘔吐発現の因果関係の検証
  堤竹蔵; 今井俊吾; 堤佳那; 山田武宏; 笠師久美子; 小林正紀; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 28, 2018年
• データマイニング手法を用いたバンコマイシンによる腎機能障害発現割合推定モデルの構築
  今井俊吾; 山田武宏; 笠師久美子; 新沼悠介; 小林正紀; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 28, 2018年
• 病院・薬局薬剤師を対象としたターミナルケアに関する態度尺度(FATCOD-Form B-J)を用いた意識調査
  熊井正貴; 加藤信太郎; 小柳遼; 久保田康生; 古堅彩子; 鳴海克哉; 小林正紀; 笠師久美子; 土居由有子; 郡修徳; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 28, 2018年
• 食品成分による記憶と腸管免疫の維持・改善に関する研究
  小林正紀; 小林正紀; 高橋夏子; 井関健, 三島海雲記念財団年次報告書, 2017, 33, 2017年11月
  日本語
• エピルビシンを用いた肝動脈化学塞栓術（TACE ）施行時の制吐薬による消化器症状の予防効果の評価
  坂本達彦; 齋藤佳敬; 小林正紀; 山田武宏; 笠師久美子; 中井正人; 小川浩司; 井関 健, 日本医療薬学会第27回年会講演要旨集, 27, 2017年11月
  研究発表ペーパー・要旨（全国大会，その他学術会議）
• 医療薬学ブラッシュアップ講座 医薬品とトランスポーターに関する話題―4―
  小林正紀, 道薬誌, 34, 7, 4‐8, 2017年07月01日
  日本語
• ビジュアル・アナログスケールを用いた「妊娠と薬相談外来」の評価
  西村 あや子; 山田 崇弘; 小林 正紀; 笠師 久美子; 井関 健, 日本医薬品情報学会総会・学術大会講演要旨集, 20回, 121, 121, 2017年06月
  (一社)日本医薬品情報学会, 日本語
• シスプラチン起因性腎障害に対するマグネシウムの軽減効果の機序
  岡本敬介; 齋藤佳敬; 小林正紀; 清水康; 秋田弘俊; 井関健, 日本医療薬学会第1 回フレッシャーズ・カンファランス要旨集, 2017年06月
  研究発表ペーパー・要旨（全国大会，その他学術会議）
• 医療薬学ブラッシュアップ講座 医薬品とトランスポーターに関する話題―3―
  小林正紀, 道薬誌, 34, 5/6, 29‐33, 2017年05月01日
  日本語
• 医療薬学ブラッシュアップ講座 医薬品とトランスポーターに関する話題―2―
  小林正紀, 道薬誌, 34, 4, 4‐8, 2017年04月01日
  日本語
• 実務実習前後における薬学生のRIASによるコミュニケーション分析
  森 綾子; 武隈 洋; 小林正紀; 山田勇磨; 佐藤夕紀; 鳴海克哉; 古堅彩子; 菅原 満, 総合技術研究会2017東京大学, 2017年03月08日
  日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）
• 食品成分による腸管免疫の維持・改善に関する研究
  窪田 篤人; 小林 正紀; 竹野 礼子; 更科 壮太; 高橋 夏子; 保田 元気; 古堅 彩子; 鳴海 克哉; 井関 健, 日本薬学会年会要旨集, 137年会, 4, 65, 65, 2017年03月
  (公社)日本薬学会, 日本語
• 医療薬学ブラッシュアップ講座 医薬品とトランスポーターに関する話題―1―
  小林正紀, 道薬誌, 34, 3, 4‐8, 2017年03月01日
  日本語
• Caco‐2細胞におけるOATP2B1基質輸送に及ぼすインスリンの影響
  小林拓; 小林正紀; 鳴海克哉; 近藤安佑子; 古堅彩子; 井関健; 井関健, 日本薬剤学会年会講演要旨集(Web), 32nd, ROMBUNNO.11‐6‐18 (WEB ONLY), 2017年
  日本語
• Caco‐2細胞におけるロキソプロフェンの輸送特性
  鳴海克哉; 小林正紀; 古堅彩子; 高橋夏子; 井関健; 井関健, 日本薬学会年会要旨集(CD-ROM), 137th, 4, ROMBUNNO.27PB‐am168, 177, 2017年
  (公社)日本薬学会, 日本語
• データマイニング手法を用いたガンシクロビル誘発性好中球減少症の要因分析
  今井 俊吾; 山田 武宏; 小林 正紀; 笠師 久美子; 井関 健, 医療薬学, 43, 10, 552, 562, 2017年
  

  Ganciclovir (GCV), an antiviral agent against cytomegalovirus infection, can cause hematological toxicity such as neutropenia. However, risk factors for neutropenia have not been well established. A decision tree (DT) model, which is a flowchart-like framework, is a data mining technique that is used to construct predictive models. In a previous study, we demonstrated its usefulness in defining prognostic factors in adverse drug reactions. Here, risk factors for GCV-induced neutropenia were analyzed using a DT model and a logistic regression model as a conventional method.

  A single-center, retrospective study was conducted at Hokkaido University Hospital. A total of 369 patients administered GCV between April 2008 and March 2017 were enrolled. Neutropenia was defined as a decrease in absolute neutrophil count (ANC) of < 1,000 cells/mm³ and to a < 75％ decrease from the baseline. All data were retrospectively collected from the electronic medical records. In the DT analysis, a chi-squared automatic interaction detection algorithm was constructed. To evaluate the established algorithms, the accuracies of each model were calculated.

  Forty (10.8％) patients developed neutropenia. Acquired immunodeficiency syndrome, hematopoietic stem cell transplantations, ANC < 6,679 cells/mm³, and duration of therapy ≥ 18 days were extracted to build the DT model, in which the patients were divided into five subgroups. Their incidence of neutropenia was 0.0 to 58.3％. The accuracies of each model were the same (89.7％), indicating that both were equally accurate.

  The results show that a useful risk prediction model for GCV-induced neutropenia can be built using DT analysis.

  , 一般社団法人日本医療薬学会, 日本語
• 製剤組成の違いがインドメタシン口腔スプレーの安定性に及ぼす影響
  田澤佑基; 鏡圭介; 渡辺祐子; 久保田康生; 原田幸子; 小林正紀; 山田武宏; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 27, 2017年
• データマイニング手法を用いたGanciclovir誘発性好中球減少症の要因分析
  今井俊吾; 山田武宏; 小林正紀; 笠師久美子; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 27, 2017年
• 血液内科疾患の治療中に生じた発熱性好中球減少症に対するテイコプラニンのトラフ値と有効性の関連性
  内山数貴; 田澤佑基; 今井俊吾; 鏡圭介; 杉田純一; 鳴海克哉; 山田武宏; 笠師久美子; 小林正紀; 豊嶋崇徳; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 27, 2017年
• 外来化学療法に対する疑義照会の新規観点別評価
  川岸亨; 久保田康生; 原田幸子; 松浦泰寛; 菅原亮輔; 吉川佳那; 堤竹蔵; 笠師久美子; 山田武宏; 小林正紀; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 27, 2017年
• プロクロルペラジンによるアカシジア発現および制吐効果に関する検討
  熊谷卓博; 齋藤佳敬; 山田武宏; 小林正紀; 熊井正貴; 笠師久美子; 小松嘉人; 井関健, 日本医療薬学会年会講演要旨集(Web), 27, 2017年
• α-Defensinが排出系トランスポータへ及ぼす影響
  保田元気; 窪田篤人; 更科壮太; 小林正紀; 井関健; 井関健; 高橋夏子, 日本医療薬学会年会講演要旨集(Web), 27, 2017年
• 院外処方せんへのがん化学療法プロトコール名掲載の取り組み
  久保田康生; 深井敏隆; 山田武宏; 小林正紀; 井関健, 北海道病院薬剤師会誌, 91, 5‐8, 8, 2016年11月25日
  保険薬局が必要とする情報を収集し、分析・解析して、稼働後に近隣保険薬局と共同で実施した講習会の内容に反映させた。さらに講習会終了後に、運用上の問題点や評価を行うためのアンケート調査を実施した。院外処方せんへ化学療法プロトコール名の印字と、薬剤部ホームページを利用した標準治療プロトコールの公開を行った。注射抗がん薬の治療内容が含まれるプロトコールほど、その理解度は低いことが示された。化学療法に関して病院からの提供が望まれる情報については四つに分類することができ、1点目は患者への服薬指導に関する項目、2点目は病院における採用薬に関する項目、3点目はプロトコールの対象がん腫や、1コースの期間・休薬期間に関する項目、4点目は患者個人に関する項目であった。アンケート結果をもとに、講習会での情報の提供内容を決定した。, (一社)北海道病院薬剤師会, 日本語
• モノカルボン酸トランスポータ4の役割に着目した疾患と副作用に関する研究
  小林正紀, 医療薬学, 42, 7, 485‐491, 491, 2016年07月10日
  

  Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems including myopathy and rhabdomyolysis, which is characterized by an elevation of creatine kinase (CK). The occurrence of myopathy has been estimated to range from 1% to 5%. The prevalence of muscular symptoms is as high as 25% among statin users who exercise. However, the mechanism by which statins cause myopathy is not precisely known. Since exercise induces the expression of monocarboxylate transporter (MCT) 4, we focused on the association between MCT4 and statin-induced muscle injury.
  This review summarizes our findings:
  1) MCT4 is a pH-dependent transporter and contributes to lactate release in RD cells as a model of in vitro skeletal muscle. AMP-activated protein kinase (AMPK) activated by exercise, increased MCT4 expression level and lactate efflux by MCT4 in RD cells and rat skeletal muscle.
  2) Statins reduce the number of viable cells and up-regulate MCT4 in RD cells. MCT4 knockdown suppresses statin-induced reduction of cell viability and apoptosis compared with negative control-treated RD cells.
  The cytotoxicity of cerivastatin, one of the statins, is associated with intracellular acidification and caspase-3/7 activation.
  3) Bicarbonate prevents cerivastatin-induced pH alteration, cytotoxicity in RD cells and muscle damage in an in vivo study.
  These results suggest that both increased expression of MCT4 and disturbance of skeletal muscle cell pH homeostasis may play an important role in statin-induced cytotoxicity.

  , 一般社団法人日本医療薬学会, 日本語
• Decision tree modelの副作用発現リスク因子解析への応用可能性に関する研究
  今井 俊吾; 山田 武宏; 笠師 久美子; 小林 正紀; 井関 健, 日本医薬品情報学会総会・学術大会講演要旨集, 19回, 83, 83, 2016年05月
  (一社)日本医薬品情報学会, 日本語
• Decision tree modelの医薬品副作用発現リスク因子解析への応用可能性に関する研究．
  今井俊吾; 山田武宏; 笠師久美子; 小林正紀; 井関健, 第63回北海道薬学大会 北海道病院薬剤師会会員研究発表会, 2016年05月
• マグネシウムによるシスプラチン起因性腎障害の軽減効果の機序に関する研究
  岡本敬介; 齋藤佳敬; 小林正紀; 清水 康; 秋田弘俊; 井関 健, 日本薬学会北海道支部第143回例会要旨集, 2016年05月
  研究発表ペーパー・要旨（全国大会，その他学術会議）
• hMCT1,4を介した基質輸送における細胞内ループの役割
  二木悠哉; 佐々木将太郎; 小林正紀; 井関健, 日本薬学会年会要旨集(CD-ROM), 136th, ROMBUNNO.27Q‐PM01S, 2016年
  日本語
• 薬剤性筋障害発生機序におけるモノカルボン酸トランスポータ4発現の関与
  小林正紀; 菊谷由里香; 木村有希; 松井統哉; 二木悠哉; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 26, 2016年
• 経口抗がん剤が腸管免疫に与える影響
  高橋夏子; 保田元気; 窪田篤人; 小林正紀; 井関健; 井関健, 日本医療薬学会年会講演要旨集(Web), 26, 2016年
• INVOLVEMENT OF NON-CONSERVED HISTIDINE RESIDUE HIS-382 IN PH REGULATION OF HUMAN SLC16A3 ACTIVITY
  Shotaro Sasaki; Masaki Kobayashi; Ken Iseki, DRUG METABOLISM REVIEWS, 47, 286, 286, 2015年11月
  英語, 研究発表ペーパー・要旨（国際会議）
• INVOLVEMENT OF MONOCARBOXYLATE TRANSPORTER 4 IN STATIN-INDUCED CYTOTOXICITY
  Masaki Kobayashi; Yurika Kikutani; Shotaro Sasaki; Ken Iseki, DRUG METABOLISM REVIEWS, 47, 180, 181, 2015年11月
  英語, 研究発表ペーパー・要旨（国際会議）
• MCTの役割に着目した疾患と副作用に関する研究
  小林正紀, 日本医療薬学会年会講演要旨集, 25th, 11, 11, 2015年10月23日
  日本医療薬学会, 日本語
• P0988-23-AM オキサリプラチンによる血管痛発現における患者背景の調査(がん薬物療法(他の副作用対策)2,ポスター,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
  坂本 和央; 久保田 康生; 速水 章一; 大江 利治; 齋藤 佳敬; 熊井 正貴; 笠師 久美子; 山田 武宏; 小松 嘉人; 柴山 良彦; 小林 正紀; 井関 健, 日本医療薬学会年会講演要旨集, 25, 430, 430, 2015年10月23日
  日本医療薬学会, 日本語
• 大豆イソフラボンによるモノカルボン酸輸送担体の阻害効果を利用したがん細胞増殖の回避戦略
  小林正紀; 佐々木将太郎; 二木悠哉; 関口穂乃佳; 鳴海克哉; 高橋夏子; 井関健; 井関健, 日本未病システム学会学術総会抄録集, 22nd, 122, 122, 2015年09月10日
  (一社)日本未病学会, 日本語
• スポーツと医学(医療),スポーツ薬理学~スポーツにおける適切な薬物治療への支援~3.薬学部における運動(スポーツ)と薬に関する教育
  小林正紀; 小林正紀, 医薬ジャーナル, 51, 7, 1723, 1725, 2015年07月01日
  日本語
• 高グルコース環境培養下での大腸癌細胞株のハロゲン置換有機酸感受性の変化
  井手野将也; 佐々木将太郎; 小林正紀; 二木悠哉; 井関健, トランスポーター研究会年会抄録集, 10th, 39, 2015年06月20日
  日本語
• 新規抗てんかん薬のLC/MS/MS定量法の確立とヒト胎盤絨毛癌由来BeWo細胞における取り込み機構の解析
  古堅 彩子; 西村 あや子; 高村 茂生; 小林 正紀; 山田 武宏; 笠師 久美子; 井関 健, 日本薬学会年会要旨集, 135年会, 4, 117, 117, 2015年03月
  (公社)日本薬学会, 日本語
• マグネシウムの経静脈前投薬によるシスプラチン起因性腎障害の予防効果の検討
  齋藤 佳敬; 小林 正紀; 山田 武宏; 笠師 久美子; 秋田 弘俊; 井関 健, 日本薬学会年会要旨集, 135年会, 4, 59, 59, 2015年03月
  (公社)日本薬学会, 日本語
• 糖尿病病態と乳酸及びアラニンの関連性
  樋口 一世; 木村 有希; 鳴海 克哉; 小林 正紀; 三好 秀明; 中村 昭伸; 渥美 達也; 笠師 久美子; 山田 武宏; 井関 健, 日本薬学会年会要旨集, 135年会, 4, 89, 89, 2015年03月
  (公社)日本薬学会, 日本語
• 持続血液ろ過透析療法中のLevofloxacinの薬物動態解析
  和田剛志; 小林正紀; 方波見謙一; 小野雄一; 前川邦彦; 柳田雄一郎; 早川峰司; 澤村淳; 井関健; 井関健; 丸藤哲, 日本集中治療医学会学術集会(Web), 42nd, DO18-5 (WEB ONLY), 2015年
  日本語
• SLC16A1発現抑制による細胞内グルタチオン量の変化
  佐々木将太郎; 木村有希; 小林正紀; 二木悠哉; 井関健, 日本薬学会年会要旨集(CD-ROM), 135th, ROMBUNNO.26U-PM04, 2015年
  日本語
• P1204-23-AM 妊娠可能年齢の女性における新世代抗てんかん薬の使用状況調査(妊婦・授乳婦,ポスター発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
  西村 あや子; 高村 茂生; 古堅 彩子; 黒川 瞳; 小林 正紀; 笠師 久美子; 山田 武宏; 井関 健, 日本医療薬学会年会講演要旨集, 25, 0, 466, 466, 2015年
  一般社団法人 日本医療薬学会, 日本語
• ダプトマイシンは骨格筋細胞におけるモノカルボン酸輸送担体の発現を低下させる
  石川 修平; 山田 武宏; 鳴海 克哉; 小林 正紀; 山口 浩明; 井関 健, 日本薬学会年会要旨集, 134年会, 3, 63, 63, 2014年03月
  (公社)日本薬学会, 日本語
• 担体介在非飽和性グルタミン輸送の評価
  佐々木将太郎; 小林正紀; 二木悠哉; 小西徹; 井関健, 生体膜と薬物の相互作用シンポジウム講演要旨集, 35th, 82, 83, 2013年11月21日
  日本語
• 抗MRSA薬ダプトマイシンの骨格筋細胞毒性に関する基礎的検討
  石川 修平; 山田 武宏; 鳴海 克哉; 小林 正紀; 山口 浩明; 井関 健, 日本薬学会年会要旨集, 133年会, 3, 169, 169, 2013年03月
  (公社)日本薬学会, 日本語
• モノカルボン酸輸送担体hMCT4の発現調節機構
  小林正紀; 鳴海克哉; 大竹翔; 佐々木将太郎; 井関健, トランスポーター研究会年会抄録集, 8th, 80, 2013年
  日本語
• モノカルボン酸輸送担体hMCT1,4の機能解析
  佐々木将太郎; 小林正紀; 二木悠哉; 井関健, トランスポーター研究会年会抄録集, 8th, 81, 2013年
  日本語
• 小腸虚血再還流により傍細胞経路からの尿酸の排泄は亢進するが, Bcrp を介した経細胞経路からの排泄は低下する
  小倉 次郎; 高橋 夏子; 小林 正紀; 山口 浩明; 井関 健, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 88, 1, 42, 42, 2013年01月01日
  日本語
• 医療現場で新しい薬剤師職能を開拓する活動(病院オペ室での活動)と教員としての研究教育活動
  小林正紀; 山田勇磨; 佐藤夕紀; 井関健, 日本医療薬学会年会講演要旨集, 22nd, 221, 221, 2012年10月10日
  日本医療薬学会, 日本語
• 手術部サテライトファーマシーにおける麻酔薬の無菌混合調製体制の確立
  山崎浩二郎; 須田範行; 新沼朋美; 水口貴史; 小林正紀; 山田勇磨; 山下美妃; 柴山良彦; 山田武宏; 井関健, 日本薬学会年会要旨集, 132nd, 4, 218, 218, 2012年03月05日
  (公社)日本薬学会, 日本語
• PKCを介した糖代謝制御およびMCT4発現変動への関連性
  大竹翔; 鳴海克哉; 小林正紀; 山口浩明; 井関健, 日本医療薬学会年会講演要旨集, 21st, 161, 161, 2011年09月09日
  日本医療薬学会, 日本語
• 抗菌薬アミカシンの用法用量別にみた治療効果の比較
  鈴木 貴宏; 川岸 亨; 小倉 次郎; 小林 正紀; 山口 浩明; 山田 武宏; 井関 健, 日本薬学会年会要旨集, 131年会, 4, 177, 177, 2011年03月
  (公社)日本薬学会, 日本語
• カラムスイッチング-LC/MS/MSによるパクリタキセル血中濃度測定法の確立
  藤川 あす歌; 山口 浩明; 伊藤 創; 田中 伸明; 古堅 彩子; 宮森 和明; 高橋 夏子; 小倉 次郎; 小林 正紀; 山田 武宏; 眞野 成康; 井関 健, 日本薬学会年会要旨集, 131年会, 4, 178, 178, 2011年03月
  (公社)日本薬学会, 日本語
• 臨床検査値の変動から推測されるスタチン系薬物由来の副作用発生率の解析研究(一般演題(口頭)43,有害事象・副作用(1),Enjoy Pharmacists' Lifestyles)
  落合 愛美; 小林 正紀; 川岸 亨; 笠師 久美子; 山口 浩明; 山田 武宏; 井関 健, 日本医療薬学会年会講演要旨集, 21, 0, 179, 179, 2011年
  一般社団法人 日本医療薬学会, 日本語
• II型糖尿病モデルラットにおける排出系トランスポーター発現変動に関する研究
  渡辺恵布; 小林正紀; 小倉次郎; 山口浩明; 井関健, 日本医療薬学会年会講演要旨集, 20th, 266, 266, 2010年10月25日
  日本医療薬学会, 日本語
• AMPK活性化が骨格筋MCT1,4発現量に及ぼす影響
  古堅彩子; 鳴海克哉; 小林正紀; 板垣史郎; 井関健, 日本薬学会年会要旨集, 130th, 4, 161, 2010年03月05日
  日本語
• 北海道大学薬学部における実務実習事前実習の取り組みとその評価
  武隈 洋; 小林 正紀; 山田 勇磨; 板垣 史郎; 吉田 和幸; 井関 健; 菅原 満, 日本薬学会年会要旨集, 130年会, 4, 346, 346, 2010年03月
  (公社)日本薬学会, 日本語
• 骨格筋における糖代謝制御~PKCを標的とした制御メカニズム~
  鳴海克哉; 古堅彩子; 渡辺恵布; 小林正紀; 板垣史郎; 井関健, 日本医療薬学会年会講演要旨集, 19th, 262, 262, 2009年09月15日
  日本医療薬学会, 日本語
• 北海道大学病院における内服薬疑義照会率の傾向と分析
  齋藤佳敬; 志賀弘康; 小林正紀; 須田範行; 菅原満; 井関健, 日本医療薬学会年会講演要旨集, 19th, 281, 2009年09月15日
  日本語
• 胃内pH変動が薬物動態に及ぼす影響―吸収予測システムによる評価―
  渡辺祐子; 井上直樹; 小林正紀; 板垣史郎; 井関健, 日本医療薬学会年会講演要旨集, 19th, 262, 262, 2009年09月15日
  日本医療薬学会, 日本語
• O9-007 がん化学療法効果減弱に寄与するP-gpの影響(一般演題 口頭発表,感染制御/持参薬管理/院内製剤/高齢者ケア/その他,医療薬学の創る未来 科学と臨床の融合)
  黒沼 圭; 小林 正紀; 高橋 夏子; 板垣 史郎; 井岡 健, 日本医療薬学会年会講演要旨集, 19, 0, 272, 272, 2009年09月15日
  日本医療薬学会, 日本語
• O13-003 北海道大学病院における内服薬疑義照会率の傾向と分析(一般演題 口頭発表,調剤・処方鑑査・リスクマネジメント/医薬品情報・データベース/有害事象・副作用,医療薬学の創る未来 科学と臨床の融合)
  齋藤 佳敬; 志賀 弘康; 小林 正紀; 須田 範行; 菅原 満; 井関 健, 日本医療薬学会年会講演要旨集, 19, 0, 281, 281, 2009年09月15日
  日本医療薬学会, 日本語
• ルテインの消化管における吸収挙動:トランスポータの関与
  佐藤夕紀; 澁谷智美; 小林正紀; 板垣史郎; 野田敏宏; 水野智; 井関健, 薬剤学, 69, Supplement, 98, 2009年04月30日
  日本語
• 小腸虚血再灌流によるP‐gp発現変動に対する食餌の影響
  小倉次郎; 藤川あす歌; 丸山創; 小林正紀; 板垣史郎; 井関健, 薬剤学, 69, Supplement, 115, 2009年04月30日
  日本語
• がん化学療法に伴う口内炎の予防・改善に有効な抗酸化物質の探索
  鷹野 瑠美; 平野 剛; 中田 千絵; 笠師 久美子; 菅原 満; 小林 正紀; 板垣 史郎; 井関 健, 医療薬学, 35, 4, 247, 253, 2009年04月
  癌化学療法に伴う口内炎の予防・改善に有効な抗酸化物質を探索するため、種々の化合物についてスーパーオキシドアニオン消去作用を評価した。対象物は含嗽として汎用されている3薬剤、抗酸化作用が記載されている8薬剤、カテキンのEGCgを用いた。その結果、含嗽剤ではアロプリノールの消去作用がレバミピドと比較して非常に強く、カモスタットはほとんど消去作用を示さなかった。他剤ではトラニラスト、メサラジン、ピロキシカムは作用が強く、ガベキサート、L-カルボシステインは弱かった。また、EGCgはアロプリノールと同等の強い消去作用を示した。次いで、組織障害に関与するラジカル連鎖反応停止作用を調べた結果、含嗽3薬剤には同作用は認めず、メサラジン、EGCgには強力な作用を認めた。更に、酸化障害性口内炎モデルに対する細胞障害抑制作用を調べたところ、EGCgは強力な効果を、アロプリノール、メサラジンは弱い効果を示し、レバミピド、カモスタットには効果を認めなかった。, (一社)日本医療薬学会, 日本語
• 多発性骨髄腫における同種造血幹細胞移植後の慢性消化管GVHDに対しベクロメタゾン腸溶性製剤を投与した症例
  久保田 康生; 小林 正紀; 笠師 久美子; 高畑 むつみ; 菅原 満; 橋野 聡; 井関 健, 医療薬学, 35, 3, 213, 218, 2009年03月
  57歳女。多発性骨髄腫を発症した。MP(メルファラン+プレドニゾロン)療法を開始し、ビスホスホネート製剤を併用したが、病勢のコントロールが不良であった。サリドマイド+デキサメタゾン療法を開始したが奏効しなかった。自己末梢血幹細胞移植は、十分なCD34陽性細胞数を得ることができず施行できなかった。サリドマイド併用によるCP(シクロホスファミド+プレドニゾロン)療法、サリドマイド併用による少量のシクロホスファミドの内服治療を順次施行したが、出血性膀胱炎などの副作用により継続できなかった。非血縁者間同種造血幹細胞移植を施行し、GVHD予防としてFK506の持続点滴を開始した。内視鏡検査と病理検査により回盲部と結腸における急性消化管GVHDの発症を確認した。プロピオン酸ベクロメタゾン(BDP)腸溶性カプセル剤を投与し、改善傾向を認めた。, (一社)日本医療薬学会, 日本語
• 乳がん化学療法プロトコルの投与スケジュールに着目した評価系の確立
  林えり子; 平野剛; 小林正紀; 板垣史郎; 井関健, 日本医療薬学会年会講演要旨集, 18th, 331, 331, 2008年09月01日
  日本医療薬学会, 日本語
• 吸収予測システムを用いた後発医薬品の薬剤学的同等性評価(2)~BCS分類Class IおよびIIIの製剤における比較~
  渡辺祐子; 山本千秋; 下山哲哉; 小林正紀; 板垣史郎; 菅原満; 平野剛; 井関健, 日本医療薬学会年会講演要旨集, 18th, 310, 310, 2008年09月01日
  一般社団法人 日本医療薬学会, 日本語
• 消化管吸収予測システムを用いた後発医薬品の薬剤学的同等性評価(1)
  下山哲哉; 渡辺祐子; 山本千秋; 小林正紀; 板垣史郎; 菅原満; 平野剛; 井関健, 日本医療薬学会年会講演要旨集, 18th, 267, 267, 2008年09月01日
  一般社団法人 日本医療薬学会, 日本語
• 放射線療法に伴う口腔粘膜障害の評価系の確立
  中田千絵; 平野剛; 鷹野瑠美; 小林正紀; 板垣史郎; 井関健, 日本医療薬学会年会講演要旨集, 18th, 252, 252, 2008年09月01日
  日本医療薬学会, 日本語
• 小腸虚血再灌流障害時における小腸吸収動態の変化
  丸山創; 小倉次郎; 小林正紀; 板垣史郎; 平野剛; 井関健, 日本医療薬学会年会講演要旨集, 18th, 265, 265, 2008年09月01日
  日本医療薬学会, 日本語
• 肝切除による有機アニオントランスポーター発現変動と遠隔臓器への影響
  藤井達郎; 板垣史郎; 小林正紀; 平野剛; 井関健, 日本医療薬学会年会講演要旨集, 18th, 265, 265, 2008年09月01日
  日本医療薬学会, 日本語
• ルテイン長期投与による肺蓄積機構の解明
  澁谷智美; 佐藤夕紀; 小林正紀; 板垣史郎; 平野剛; 井関健, 日本医療薬学会年会講演要旨集, 18th, 280, 280, 2008年09月01日
  日本医療薬学会, 日本語
• 20D-28 放射線療法に伴う口腔粘膜障害の評価系の確立(がん薬物療法(副作用対策),来るべき時代への道を拓く)
  中田 千絵; 平野 剛; 鷹野 瑠美; 小林 正紀; 板垣 史郎; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 252, 252, 2008年09月01日
  日本医療薬学会, 日本語
• 20I-24 小腸虚血再灌流障害時における小膓吸収動態の変化(薬物動態(基礎),来るべき時代への道を拓く)
  丸山 創; 小倉 次郎; 小林 正紀; 板垣 史郎; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 265, 265, 2008年09月01日
  日本医療薬学会, 日本語
• 20I-25 肝切除による有機アニオントランスポーター発現変動と遠隔臓器への影響(薬物動態(基礎),来るべき時代への道を拓く)
  藤井 達郎; 板垣 史郎; 小林 正紀; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 265, 265, 2008年09月01日
  日本医療薬学会, 日本語
• 21C-12 消化管吸収予測システムを用いた後発医薬品の薬剤学的同等性評価(1)(後発医薬品,来るべき時代への道を拓く)
  下山 哲哉; 渡辺 祐子; 山本 千秋; 小林 正紀; 板垣 史郎; 菅原 満; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 267, 267, 2008年09月01日
  日本医療薬学会, 日本語
• 21I-13 ルテイン長期投与による肺蓄積機構の解明(薬物動態(基礎・臨床・遺伝子多型),来るべき時代への道を拓く)
  澁谷 智美; 佐藤 夕紀; 小林 正紀; 板垣 史郎; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 280, 280, 2008年09月01日
  日本医療薬学会, 日本語
• 20-P1-168 吸収予測システムを用いた後発医薬品の薬剤学的同等性評価(2) : BCS分類class IおよびIIIの製剤における比較(後発医薬品,来るべき時代への道を拓く)
  渡辺 祐子; 山本 千秋; 下山 哲哉; 小林 正紀; 板垣 史郎; 菅原 満; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 310, 310, 2008年09月01日
  日本医療薬学会, 日本語
• 20-P2-290 乳がん化学療法プロトコルの投与スケジュールに着目した評価系の確立(がん薬物療法(その他),来るべき時代への道を拓く)
  林 えり子; 平野 剛; 小林 正紀; 板垣 史郎; 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 331, 331, 2008年09月01日
  日本医療薬学会, 日本語
• スタチン系薬物間における筋障害およびコレステロール低下作用の比較
  知嵜郁美; 小林正紀; 板垣史郎; 平野剛; 井関健, J Toxicol Sci, 33, Supplement, S169, 2008年06月
  日本語
• N‐モノデスエチルアミオダロンの肺細胞への取り込み機構と肺障害性との関連
  関悟; 板垣史郎; 小林正紀; 平野剛; 井関健, 薬剤学, 68, Supplement, 268, 2008年04月30日
  日本語
• 北大病院における内服薬疑義照会率の傾向と分析
  齋藤 佳敬; 榊原 則寛; 志賀 弘康; 沖 洋充; 小林 正紀; 川合 真次; 深井 敏隆; 菅原 満; 井関 健, 日本薬学会年会要旨集, 128年会, 4, 163, 163, 2008年03月
  (公社)日本薬学会, 日本語
• 20D-30 がん化学療法における口内炎の予防に対する抗酸化物質の応用(がん薬物療法(副作用対策),来るべき時代への道を拓く)
  鷹野 瑠美; 平野 剛; 中田 千絵; 笠師 久美子; 菅原 満; 小林 正紀; 板垣 史郎; 井関 健; 大江 利治, 日本医療薬学会年会講演要旨集, 18, 0, 253, 253, 2008年
  一般社団法人 日本医療薬学会, 日本語
• 20D-30 がん化学療法における口内炎の予防に対する抗酸化物質の応用(がん薬物療法(副作用対策),来るべき時代への道を拓く)
  鷹野 瑠美; 平野 剛; 中田 千絵; 笠師 久美子; 菅原 満; 小林 正紀; 板垣 史郎; 井関 健; 大江 利治, 日本医療薬学会年会講演要旨集, 18, 0, 253, 253, 2008年
  一般社団法人 日本医療薬学会, 日本語
• 29-C1-10-2 Coenzyme Q10の消化管吸収挙動:排出系トランスポーターの関与(薬物相互作用・薬物動態,社会の期待に応える医療薬学を)
  落合 彰子; 小林 正紀; 板垣 史郎; 平野 剛; 菅原 満; 井関 健, 日本医療薬学会年会講演要旨集, 17, 196, 196, 2007年09月01日
  日本医療薬学会, 日本語
• 29-C1-10-4 ルテインの吸収動態の解明と酸化障害抑制効果に対する検討(薬物相互作用・薬物動態,社会の期待に応える医療薬学を)
  佐藤 夕紀; 澁谷 智美; 小林 正紀; 板垣 史郎; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 17, 196, 196, 2007年09月01日
  日本医療薬学会, 日本語
• 30-A2-13-5 小腸虚血再灌流によるABCトランスポーター発現変動(がん薬物療法・薬物動態,社会の期待に応える医療薬学を)
  小倉 次郎; 小林 正紀; 板垣 史郎; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 17, 199, 199, 2007年09月01日
  日本医療薬学会, 日本語
• 細胞内シグナル伝達系を介したMCT1,4の調節機構
  鳴海克哉; 小林正紀; 香川俊樹; 板垣史郎; 平野剛; 井関健, 薬剤学, 67, Supplement, 260, 260, 2007年05月10日
  日本語
• ABCG2プロモータ活性に及ぼす性ホルモンの影響
  安田哲; 小林正紀; 板垣史郎; 平野剛; 井関健, 薬剤学, 67, Supplement, 258, 258, 2007年05月10日
  日本語
• トランスポーター活性制御によるアミオダロンの肺障害性の軽減
  関 悟; 板垣 史郎; 小林 正紀; 平野 剛; 井関 健, 薬剤学 = Journal of Pharmaceutical Science and Technology, Japan, 67, 244, 244, 2007年05月10日
  日本語
• 30-D-05 多発性骨髄腫患者に対するサリドマイド経口投与後の両エナンチオマー血中濃度測定方法の確立(癌薬物療法(外来化学療法、緩和ケア等),医療薬学の扉は開かれた)
  千本木 要; 田中 雅則; 櫻田 惠右; 小林 正紀; 板垣 史郎; 平野 剛; 井関 健, 日本医療薬学会年会講演要旨集, 16, 0, 315, 315, 2006年09月01日
  日本医療薬学会, 日本語
• Pravastatinおよびrosuvastatinの骨格筋細胞障害性にpH変動が及ぼす影響
  小林正紀; 香川俊樹; 鷹野瑠美; 板垣史郎; 平野剛; 井関健, J Toxicol Sci, 31, Supplement, S113, 2006年06月10日
  日本語
• ヒトPEPT1の安定大量発現系の構築とその有用性
  藤沢佑紀; 館岡涼子; 宮内正二; 久保さやか; 大塚幸夫; 小林正紀; 井関健; 奈良敏文; 加茂直樹, 生体膜と薬物の相互作用シンポジウム講演要旨集, 23rd, 205, 208, 2001年11月08日
  日本語

• 卒業研究準備実習Ⅰ, 2024年, 学士課程, 薬学部
• 生命医薬科学概論, 2024年, 修士課程, 生命科学院
• 卒業研究準備実習Ⅱ, 2024年, 学士課程, 薬学部
• 生命倫理学特論, 2024年, 修士課程, 生命科学院
• 薬学論文講読演習Ⅰ, 2024年, 学士課程, 薬学部
• 大学院共通授業科目（一般科目）：複合領域, 2024年, 修士課程, 大学院共通科目
• 薬学論文講読演習Ⅱ, 2024年, 学士課程, 薬学部
• 臨床がん化学療法特論, 2024年, 博士後期課程, 生命科学院
• 薬学論文講読演習Ⅲ, 2024年, 学士課程, 薬学部
• 臨床薬学外国語コミュニケーション特別演習, 2024年, 博士後期課程, 生命科学院
• 薬学総合演習, 2024年, 学士課程, 薬学部
• 臨床薬学特別講義, 2024年, 博士後期課程, 生命科学院
• 薬学卒業研究, 2024年, 学士課程, 薬学部
• 薬学倫理特論, 2024年, 博士後期課程, 生命科学院
• 薬科学演習, 2024年, 学士課程, 薬学部
• 栄養薬理学特論, 2024年, 博士後期課程, 生命科学院
• 薬科学論文講読演習, 2024年, 学士課程, 薬学部
• 臨床薬学実習, 2024年, 博士後期課程, 生命科学院
• 薬科学卒業研究, 2024年, 学士課程, 薬学部
• 臨床薬学技術実習, 2024年, 博士後期課程, 生命科学院
• 生命科学特別研究, 2024年, 博士後期課程, 生命科学院
• 薬物治療学特論, 2024年, 博士後期課程, 生命科学院
• 生命科学文献講読, 2024年, 博士後期課程, 生命科学院
• 臨床薬学事前演習, 2024年, 学士課程, 薬学部
• 臨床薬学特別研究, 2024年, 博士後期課程, 生命科学院
• 医療概論, 2024年, 学士課程, 薬学部
• 臨床薬学論文講読Ⅰ, 2024年, 博士後期課程, 生命科学院
• 薬剤経済学, 2024年, 学士課程, 薬学部
• 臨床薬学論文講読Ⅱ, 2024年, 博士後期課程, 生命科学院
• 薬物治療学Ⅱ, 2024年, 学士課程, 薬学部
• 臨床薬学論文執筆演習, 2024年, 博士後期課程, 生命科学院
• 薬物治療学Ⅲ, 2024年, 学士課程, 薬学部
• 臨床生薬学特論, 2024年, 博士後期課程, 生命科学院
• 認定MR演習/認定CRC演習, 2024年, 学士課程, 薬学部
• 社会薬学特別講義, 2024年, 博士後期課程, 生命科学院
• 医療情報解析演習, 2024年, 学士課程, 薬学部
• 薬局実習, 2024年, 学士課程, 薬学部
• 臨床薬物動態解析演習, 2024年, 学士課程, 薬学部
• 薬事関連法規, 2024年, 学士課程, 薬学部
• 病院実習, 2024年, 学士課程, 薬学部

• クロザピン誘発性流涎症(CIS)の発現機序の解明と新規治療法の開発
  2021年度 「薬学系研究継続助成」
  2021年 - 2024年
  小林正紀、石川修平
  公益財団法人 武田科学振興財団
• エネルギー源輸送を担うMCTsの機能解析と治療薬の探索
  科学研究費助成事業 基盤研究(C)
  2020年 - 2023年
  小林 正紀
  本邦において高齢者に頻発する糖尿病や認知症等の疾患に対する有効な予防・治療法の開発が求められている。この対策として栄養介入による効果を期待するものが数多く報告され、これは生体内のエネルギー源の重要性を示唆するものである。最近エネルギー源として認知されてきた乳酸やピルビン酸とこれらを輸送するヒトモノカルボン酸輸送担体（hMCT）は、上記疾患と関連することが示唆されている。しかしながらhMCTの機能および生体内の役割については未だ不明な点が多い。そこで本研究ではhMCTの中でもhMCT2, 11に着目し、細胞における機能・発現を明らかにすることで、これらを標的とした化合物の探索を行う。昨年度は、hMCT2の評価系の樹立に成功したことから、今年度はhMCT11の評価系の構築を目的とするとともに、臨床研究における知見との比較・考察を試みた。
  日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 20K07171
• 腸管免疫に関わる新たな指標を用いたOTC薬の安全性評価
  2020年 - 2021年
  小林正紀
  公益財団法人一般用医薬品セルフメディケーション振興財団, 研究代表者
• クロザピン誘発性流涎症(CIS)の発現機序の解明と新規治療法の開発
  2019年度 「薬学系研究助成」
  2019年 - 2021年
  小林正紀
  公益財団法人 武田科学振興財団, 研究代表者
• 食品成分による分子標的薬のリスク回避と免疫予測マーカーの探索
  科学研究費助成事業
  2017年 - 2021年
  鈴木 夏子; 小林 正紀
  本研究では、分子標的薬曝露後のalpha defensin (Defa)5および toll-like receptor (TLR) 4発現量の変動、Defa5の産生を促進する食品成分の探索、さらに分子標的薬による腸管免疫低下に対する食品成分の有用性を評価した。分子標的薬の曝露により、Defa5およびTLR4タンパク質発現量は有意に減少した。また、食品成分曝露によるDefa等への影響については、一部の食品成分でDefa5およびTLR4タンパク質発現量を増加させることを見出した。最後に、食品成分を併用することで、分子標的薬による腸管免疫低下を回復する可能性が示唆された。
  日本学術振興会, 基盤研究(C), 研究分担者, 17K00871
• 新規糖尿病関連遺伝子MCT11の機能解析と遺伝子多型が薬物治療効果に及ぼす影響の解明
  2019年 - 2020年
  小林正紀
  公益財団法人 政策医療振興財団, 研究代表者
• 食品成分の抗酸化作用に着目した記憶・腸管免疫賦活作用の機序に関する研究
  2019年研究助成
  2019年 - 2020年
  小林正紀
  一般財団法人 旗影会, 研究代表者, 競争的資金
• コーヒー成分が記憶形成と腸管免疫に及ぼす影響に関する研究
  2018年助成対象研究
  2018年 - 2019年
  小林正紀
  一般社団法人 全日本コーヒー協会, 研究代表者, 競争的資金
• 食品成分のα-ディフェンシン分泌促進作用による小腸移植後感染症の予防戦略
  科学研究費助成事業 基盤研究(C)
  2016年 - 2019年
  井関 健; 小林 正紀
  本研究では、小腸虚血再還流(I/R)後のalpha-defensin (Defa)5産生量の変動、Defa5産生促進物質の探索、食品成分のDefa5産生促進作用による小腸I/R予防効果の3点について行ってきた。最初の検討により小腸I/R処置において小腸絨毛の顕著な脱落と炎症性マーカーの上昇を確認し、本条件下においてDefa5 mRNA量が有意に低下することを見出した。一方で一部の食品成分がDefa5 mRNA量を増大させることを明らかとした。最後に本食品成分をI/R前に前投与することで、I/Rによる腸管免疫低下ならびに絨毛の脱落を軽減させることを見出した。
  日本学術振興会, 基盤研究(C), 北海道大学, 研究分担者, 16K08388
• 食品成分による記憶と腸管免疫の維持・改善に関する研究
  平成28年度学術研究奨励金
  2016年 - 2017年
  小林正紀
  公益財団法人 三島海雲記念財団, 研究代表者, 競争的資金
• MCTの機能・発現阻害に基づいたがん細胞の転移・浸潤の抑制効果の検証
  基盤研究(C)
  2015年 - 2017年
  小林正紀
  独立行政法人 日本学術振興会, 研究代表者, 競争的資金
• 胆汁酸の輸送特性を反映した胎児毒性の回避戦略
  2015年度 研究助成
  2015年 - 2016年
  小林正紀
  公益財団法人 秋山記念生命科学振興財団, 研究代表者, 競争的資金
• 5 -オキソプロリンの輸送担体を利用したグリア細胞の酸化ストレス抵抗性に関する研究
  2015年 研究助成
  2015年 - 2016年
  小林正紀
  一般財団法人 旗影会, 研究代表者, 競争的資金
• 薬剤性筋障害の早期発見を目的としたバイオマーカーの探索と臨床応用
  平成26年度研究助成
  2014年 - 2015年
  小林正紀
  一般財団法人 横山臨床薬理研究助成基金, 研究代表者, 競争的資金
• 記憶の維持・改善を指向した食品成分によるエネルギー源輸送の阻害・促進メカニズムの解明
  平成26年度公募研究
  2014年 - 2015年
  小林正紀
  一般財団法人 糧食研究会, 研究代表者, 競争的資金
• 大豆ポリフェノールによる乳酸輸送担体の阻害を利用したがんの浸潤・転移の回避戦略
  平成26年度 研究助成
  2014年 - 2014年
  小林正紀
  タカノ財団, 研究代表者, 競争的資金
• 乳酸輸送体の機能解析と個別化治療へ向けた臨床応用に関する研究
  若手研究人材・ネットワーク育成補助金
  2013年 - 2014年
  小林正紀
  ノーステック財団, 研究代表者, 競争的資金
• 乳酸輸送担体(MCT)の基質認識性の解明および機能解析に基づく薬剤性筋障害制圧へ向けた新規戦略
  若手研究者自立支援
  2013年 - 2013年
  小林正紀
  北海道大学重点配分経費, 研究代表者, 競争的資金
• 筋MCTの役割に着目した薬剤性筋障害の回避戦略
  科学研究費補助金(若手研究(B))
  2012年 - 2013年
  小林正紀
  文部科学省, 研究代表者, 競争的資金
• トランスポータの発現変動を利用した薬物濃度調節
  第23回中富健康科学振興財団・研究助成金
  2010年 - 2011年
  小林正紀
  公益財団法人 中富健康科学振興財団, 研究代表者, 競争的資金
• 骨格筋細胞内pH調節因子の評価培養系モデルの構築
  笹川科学研究助成
  2009年 - 2010年
  小林正紀
  公益財団法人 日本科学協会, 研究代表者, 競争的資金
• 糖尿病治療を標的としたGLUTおよびMCT発現調節機構解明
  若手研究人材・ネットワーク育成補助金
  2008年 - 2009年
  小林正紀
  ノーステック財団, 研究代表者, 競争的資金
• 高脂血症薬の副作用回避ストラテジーの構築～新規薬物相互作用の解明～
  科学研究費補助金(若手研究(B))
  2008年 - 2009年
  小林正紀
  本研究はトランスポータの発現制御を担う核内受容体LXR(liver X receptor)に着目し、LXRの活性に影響を及ぼす脂質異常症治療薬(スタチン)投与時の薬物動態変動の可能性を明らかにし、薬物-薬物相互作用の要因の一端を明らかにすることを目的としている。本研究により脂質異常症に対する安全かつ適正な薬物治療の一助となる。
  文部科学省, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 20790126

• 糖の吸収抑制用剤
  特許権, 鳴海克哉; 小林正紀; 井関健; 佐藤浩志; 盛孝男
  特願2021-86743, 2021年05月24日
  特開2022-179925, 2022年12月06日
  特許7428991, 2024年01月30日