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鳴海 克哉 (ナルミ カツヤ)
| 薬学研究院 医療薬学部門 医療薬学分野 | 准教授 |
研究者基本情報
■ 学位■ URL
researchmap URLホームページURL■ ID 各種
J-Global ID■ 研究キーワード・分野
研究分野■ 担当教育組織
研究活動情報
■ 受賞- 2025年06月, 公益財団法人 サッポロ生物科学振興財団 奨励賞
- 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ポジウム 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―
41929706 - 2018年05月, 平成30年度 日本薬学会北海道支部 奨励賞
- 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 : official journal of the European Federation for Pharmaceutical Sciences, 107565, 107565, 2026年05月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Fetal exposure to anesthetics via the placenta during the perinatal period may adversely affect central nervous system development. Organic anion-transporting polypeptide 2B1 (OATP2B1) functions as an active transport carrier across the blood-placental barrier and can be modulated by interactions with rosuvastatin (RSV). This study hypothesized that drug interactions could alter OATP2B1-mediated transport of remimazolam (RMZ), thereby modulating its placental permeability. First, an in vitro 3D blood-placental barrier model was used to assess the permeability of RMZ with a single administration (100 nM RMZ) and co-administration with RSV (0.1, 1, and 10 nM). RMZ permeability was significantly decreased from 2 to 4 hours in the RMZ alone group (p < 0.001), whereas at 3-4 hours post-dose it was significantly decreased by 15-71% in the groups treated with 1 nM or 10 nM RSV in combination, compared to the RMZ alone group. Next, intracellular uptake assays using OATP2B1-overexpressing human embryonic kidney 293 cells (HEK293) confirmed carrier-mediated transport of RMZ. Uptake was time-dependent, markedly higher than in non-expressing cells, and decreased by 57.6-61.1% in the presence of RSV. These findings demonstrate that RMZ is transported via OATP2B1 through a non-high-affinity binding site and that placental transfer of RMZ can be modulated by drug interactions that alter OATP2B1 function. Considering the differences in OATP2B1 localization between in vivo and in vitro conditions, modification of OATP2B1 transport function by RSV may potentially contribute to increased fetal exposure to RMZ at the blood-placental barrier. - 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
研究論文（学術雑誌） - 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, 2026年01月24日, ［査読有り］, ［国際誌］
英語, 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, in press, 2026年01月09日, ［査読有り］, ［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. UPLC-MS/MS 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., 46258738 - 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］, ［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. - Corrigendum to "Quantitative analysis of communication changes in online medication counseling using the Roter Interaction System" [Res Soc Adm Pharm 20 (2024) 36-42].
Ayako Mori; Izumi Kato; Katsuya Narumi; Yoh Takekuma; Hitoshi Kashiwagi; Yuki Sato; Mitsuru Sugawara; Masaki Kobayashi
Research in social & administrative pharmacy : RSAP, 2025年12月19日, ［国際誌］
英語 - 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］, ［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., 41929706 - 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］, ［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］, ［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05月23日, ［査読有り］, ［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］
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］, ［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］, ［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., 41929706 - 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］, ［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. - Reply to Accurate 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, 2024年11月03日, ［国際誌］
英語 - 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］
研究論文（学術雑誌） - 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］, ［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. - 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 & pharmaceutical bulletin, 47, 9, 1477, 1483, 2024年09月, ［査読有り］, ［筆頭著者, 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., 29449672 - 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08月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Pharmaceutical care is important for mental health during the perinatal period, which is often characterized by insomnia. In recent years, prescriptions of melatonin receptor agonists (MRAs) and dual orexin receptor antagonists (DORAs) for insomnia have increased; however, their use during the perinatal period has scarcely been reported. In the present study, we developed a UPLC-MS/MS method for the quantification of ramelteon, its metabolite M-II, suvorexant, and lemborexant in human plasma and breast milk to accumulate information on the safety and transfer of MRAs and DORAs into breast milk. Samples of MRAs (ramelteon and M-II) in plasma and breast milk were prepared using liquid-liquid extraction (LLE) with ethyl acetate. For DORAs (suvorexant and lemborexant), LLE with ethyl acetate was applied to plasma samples. For breast milk samples, significant ion suppression was observed for LLE with ethyl acetate. Solid-phase extraction (SPE) cartridges capable of removing phospholipids improved the matrix effects. Finally, protein precipitation with methanol and an SPE cartridge, InertSep® Phospholipid Remover, were selected for breast milk sample preparation. An ACQUITY UPLC BEH C18 column was used for analyte separation. MRAs and DORAs were eluted using isocratic and gradient elution, respectively, and analyzed using electrospray ionization in the positive mode with multiple reaction monitoring. The range of calibration curve for MRAs and DORAs was 0.1-25 and 0.5-50 ng/ml, respectively. Both the plasma and breast milk samples exhibited good linearity over this range. The method was validated by evaluating its accuracy and precision, matrix effect, recovery, carry-over, stability, and dilution integrity. The validated method was successfully applied to clinical samples donated by breastfeeding women and the milk/plasma (M/P) ratio and relative infant dose (RID) of lemborexant (one case) and suvorexant (two cases) were estimated. The M/P ratio of lemborexant was <1, and the RID was 1.05 %. The M/P ratio of suvorexant was <0.1, and RID was 0.11-0.20 %. This method will be useful for future studies evaluating the safety of these drugs during breastfeeding. - 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, (一社)日本TDM学会, 2024年07月
日本語 - 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］, ［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., 41929706 - 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］, ［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. - 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 & pharmaceutical bulletin, 47, 4, 764, 770, Pharmaceutical Society of Japan, 2024年04月04日, ［国内誌］
英語, 研究論文（学術雑誌）, L-Lactate transport via monocarboxylate transporters (MCTs) in the central nervous system, represented by the astrocyte-neuron lactate shuttle (ANLS), is crucial for the maintenance of brain functions, including memory formation. Previously, we have reported that MCT1 contributes to L-lactate transport in normal human astrocytes. Therefore, in this study, we aimed to identify transporters that contribute to L-lactate transport in human neurons. SH-SY5Y cells, which are used as a model for human neurons, were differentiated using all-trans-retinoic acid. L-Lactate uptake was measured using radiolabeled L-lactate, and the expression of MCT proteins was confirmed Western blotting. L-Lactate transport was pH-dependent and saturated at high concentrations. Kinetic analysis suggested that L-lactate uptake was biphasic. Furthermore, MCT1, 2 selective inhibitors inhibited L-lactate transport. In addition, the expression of MCT1 and 2 proteins, but not MCT4, was confirmed. In this study, we demonstrated that MCT1 and 2 are major contributors to L-lactate transport in differentiated human neuroblastoma SH-SY5Y cells from the viewpoint of kinetic analysis. These results lead to a better understanding of ANLS in humans, and further exploration of the factors that can promote MCT1 and 2 functions is required. - 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］, ［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. - 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, 334, 122205, 122205, Elsevier BV, 2023年10月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Human monocarboxylate transporter 9 (hMCT9), encoded by SLC16A9, is a transporter that mediates creatine transport across the transmembrane. Previously, we reported that hMCT9 is an extracellular pH- and Na+-sensitive creatine transporter with two kinetic components. Recently, some variants of hMCT9 have been found to be associated with serum uric acid levels, hyperuricemia, and gout. Among these, two single-nucleotide polymorphisms (SNPs) have also been reported: rs550527563 (L93M) and rs2242206 (T258K). However, the effect of these SNPs on hMCT9 transport activity remains unclear. This study aimed to determine the influence of hMCT9 L93M and T258K on transport characteristics. MAIN METHODS: hMCT9 L93M and T258K were constructed by site-directed mutagenesis and expressed in Xenopus laevis oocyte. Transport activity of uric acid and creatine via hMCT9 were measured by using a Xenopus laevis oocyte heterologous expression system. KEY FINDINGS: We assessed the transport activity of uric acid and creatine and observed that hMCT9-expressing oocytes weakly transported uric acid approximately 3- to 4-fold more than water-injected oocytes. hMCT9 L93M slightly reduced the transport activity of creatine, whereas hMCT9 T258K did not affect the transport activity. Interestingly, hMCT9 T258K abolished Na+ sensitivity and altered the substrate affinity from two components to one. SIGNIFICANCE: In conclusion, hMCT9 SNPs affect transport activity and characteristics. hMCT9 L93M and T258K may induce dysfunction and contribute to pathologies such as hyperuricemia and gout. This is a first study to evaluate molecular characteristics of hMCT9 SNPs. - 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］, ［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. - 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］, ［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］, ［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］, ［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］, ［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］, ［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］, ［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., 29449355 - 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］
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. - 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］, ［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］, ［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: the biological fate of chemicals, 2022年07月16日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Aldehyde oxidase 1 (AOX1) is a molybdenum-containing enzyme that catalyzes the oxidation of a range of aldehyde compounds and clinical drugs, including azathioprine and methotrexate. The purpose of this study was to elucidate the effects of single-nucleotide polymorphisms (SNPs) in the coding regions of the human AOX1 gene on protein dimer formation and metabolic activity. Six variants (Q314R [rs58185012], I598N [rs143935618], T755I [rs35217482], A1083G [rs139092129], N1135S [rs55754655], and H1297R [rs3731722]), with allele frequencies greater than 0.01 in 1 or more population, were obtained from the genome aggregation and 1000 Genomes project databases. Protein expression and dimer formation were evaluated using HEK293T cells expressing the wild-type (WT) or different SNP variants of AOX1. Kinetic analyses of phthalazine oxidation were performed using S9 fractions of HEK293T cells expressing WT or each the different mutant AOX1. Although we detected no significant differences among WT AOX1 and the different variants with respect to total protein expression, native PAGE analysis indicated that one of the SNP variants, T755I, found in East Asian populations, dimerizes less efficiently than the WT AOX1. Kinetic analysis, using phthalazine as a typical substrate, revealed that this mutation contributes to a reduction in the maximal rates of reaction without affecting enzyme affinity for phthalazine. Our observation thus indicates that the T755I variant has significantly negative effects on both the dimer formation and in vitro catalytic activity of AOX1. These findings may provide valuable insights into the mechanisms underlying the inter-individual differences in the therapeutic efficacy or toxicity of AOX1 substrate drugs. Significance Statement The T755l (rs35217482) SNP variant of the AOX1 protein, which is prominent in East Asian populations, suppresses protein dimer formation, resulting in a reduction in the reaction velocity of phthalazine oxidation to less than half of that of wild-type AOX1. - 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］, ［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］, ［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. - [Development of an Online Role-play-based Medical Interview Training Method for Fourth-year Pharmacy Students].
Ayako Mori; Izumi Kato; Hitoshi Kashiwagi; Shungo Imai; Katsuya Narumi; Yuki Sato; Ayako Furugen; Yuma Yamada; Masaki Kobayashi
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 142, 6, 661, 674, 2022年, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, With the coronavirus disease 2019 pandemic, businesses are rapidly expanding their online practices, and the online medical care system has been established and is growing. The field of pharmacy education is also looking for ways to conduct practical online training. Hence, we developed an online role-play-based medical interview training method for fourth-year pharmacy students. The purpose of this study was to describe in detail this method and to clarify the effect of online on medical interviewing practice. The training sessions were conducted using video teleconferencing software. Two settings were used for the role-play scenarios: the pharmacy and hospital. To evaluate the effectiveness of the sessions, a questionnaire was sent to the students, and the results were analyzed using text mining. The most important requirement for successfully conducting the interviews was a stable voice connection, and we reduced audio interruptions and delays by connecting the host personal computer to a wired local area network. We also solved the problem of howling when multiple terminals were installed in the same room by muting all devices in the room. Results of the analysis of the questionnaires suggested that students were more tense online. We also found that students perceived a difference between online and face-to-face interviews in terms of eye contact and the presentation of documents. In this way, we succeeded in conducting smooth online role-playing sessions while taking countermeasures against infection. In the future, it will be necessary to devise nonverbal communication methods and digital methods of presenting the training material. - 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, 8, 2021年08月24日, ［査読有り］, ［責任著者］, ［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. - 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］, ［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. - 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］, ［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］, ［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. - 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］, ［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］, ［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］, ［責任著者］, ［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］, ［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］, ［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］, ［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. - Analysis of alpha-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02月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌） - 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］, ［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. - 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11月, ［査読有り］, ［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 of 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 the 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, but 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. - 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, 72, 5, 1426, 1432, 2020年10月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 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10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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］, ［国際誌］
英語, 研究論文（学術雑誌） - 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］, ［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. - 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, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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］, ［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. - 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］, ［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. - 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10月, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌） - 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］, ［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%. - 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） - 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; 井関健
日本緩和医療薬学雑誌, 12, 1, 1, 8, (一社)日本緩和医療薬学会, 2019年, ［査読有り］
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 Roter method of interaction process analysis(RIAS)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
薬学雑誌, 138, 12, 1579, 1586, 2018年12月, ［査読有り］, ［国内誌］
日本語 - 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］, ［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. - 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］, ［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. - 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. - 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］, ［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］, ［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. - 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］, ［筆頭著者］, ［国際誌］
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］, ［国際誌］
英語, 研究論文（学術雑誌） - 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］, ［国際誌］
英語, 研究論文（学術雑誌） - The flexible cytoplasmic loop 3 contributes to the substrate affinity of human monocarboxylate transporters.
Futagi Y; Sasaki S; Kobayashi M; Narumi K; Furugen A; Iseki K
Biochimica et biophysica acta, 1859, 10, 1790, 1795, 2017年05月, ［査読有り］ - 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］, ［国際誌］
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］, ［国際誌］
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 (Elmsford, N.Y.), 67, 48, 55, 2017年01月, ［査読有り］, ［国際誌］
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.
Kaneko C; Ogura J; Sasaki S; Okamoto K; Kobayashi M; Kuwayama K; Narumi K; Iseki K
Biochimica et biophysica acta, 1861, 3, 559, 566, 2016年11月, ［査読有り］ - 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］, ［筆頭著者］, ［国際誌］
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］, ［国際誌］
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］, ［国際誌］
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, 9, 2016年04月, ［査読有り］, ［国際誌］
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］, ［国際誌］
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, 33, 2015年10月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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］, ［国内誌］
英語, 研究論文（学術雑誌） - 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~4.薬学研究から提言するスポーツと薬について
鳴海克哉
医薬ジャーナル, 51, 7, 87, 90, 医薬ジャーナル社, 2015年
日本語 - 消化管GVHD(graft-versus-host disease)に対する経口ベクロメタゾン製剤の有用性の検討
久保田康生; 鳴海克哉; 笠師久美子; 山田武宏; 岡田耕平; 重松明男; 豊嶋崇徳; 伊関健; 伊関健
医療薬学, 40, 5, 291, 296, (一社)日本医療薬学会, 2014年, ［査読有り］
日本語, 同種造血幹細胞移植後に消化管移植片対宿主病(GVHD)を発症し、プロピオン酸ベクロメタゾン(BDP)を投与した急性GVHD 21例と慢性GVHD 8例について後方視的に検討した。BDP製剤内服後の全体の消化管GVHD改善率は69.0%で、急性GVHDでは消化管障害のstage分類が高くなるほど改善率は低下した。慢性GVHDでは急性GVHDよりも消化管GVHDの発症時期が遅く、BDP製剤の内服期間が長かったが、stage分類による効果の差はなかった。また、遺伝子型HALの合致度によるBDPの効果に差はなく、GVHDの重症度が高いほど全身性ステロイドの使用率が高かったが、全身性ステロイドの使用状況とサイトメガロウイルス抗原血症陽性率に差はなかった。stageが低い段階から可及的早期にBDP製剤を導入することで消化管GVHDの症状改善と局所制御が期待できると考えられた。 - 病棟薬剤師による持参薬業務の評価
難波正志; 樋口一世; 鳴海克哉; 関悟; 山田順子; 笠師久美子; 深井敏隆; 山田武宏; 井関健; 井関健
北海道病院薬剤師会誌, 87, 11, 13, (一社)北海道病院薬剤師会, 2014年, ［査読有り］
日本語 - 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］, ［国内誌］
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］, ［筆頭著者］, ［国際誌］
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, 8, 2011年01月17日, ［査読有り］, ［国際誌］
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, 73, 2010年, ［査読有り］, ［筆頭著者］, ［国内誌］
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, 75, 2008年04月23日, ［査読有り］, ［国際誌］
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］ - 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 & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 11, 1, 1, 8, 2008年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）
- 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; 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 - 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 - 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; 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 - 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 - 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 - 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 - 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 - 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, 3, ROMBUNNO.27U‐am06S, 76, 2018年03月, ［査読有り］
(公社)日本薬学会, 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 - 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(CD-ROM), 32nd, 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 - 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, ［査読有り］
(一社)日本未病システム学会, 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〜】薬学研究から提言するスポーツと薬について
鳴海 克哉, 医薬ジャーナル, 51, 7, 1727, 1730, 2015年07月
(株)医薬ジャーナル社, 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 - 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 - 消化管GVHDに対する経口ベクロメタゾン製剤の有用性の検討
久保田康生; 鳴海克哉; 笠師久美子; 山田武宏; 岡田耕平; 重松明男; 豊嶋崇徳; 井関健; 井関健, 日本造血細胞移植学会総会プログラム・抄録集, 36th, 2014年 - チゲサイクリンとコリスチンの併用が奏功した多剤耐性アシネトバクター・バウマニによるカテーテル関連血流感染症の1例
山田武宏; 山田武宏; 白鳥聡一; 杉田純一; 藤本勝也; 豊嶋崇徳; 福元達也; 岩崎澄央; 秋沢宏次; 鳴海克哉; 石黒信久; 井関健; 井関健, 日本化学療法学会雑誌, 62, 4, 501, 505, 2014年
(公社)日本化学療法学会, 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 - 理解しやすい服薬指導を目指した当薬局での取り組み~外用薬の使用方法について~
高橋正幸; 平野卓哉; 瀧本瑞恵; 加藤由紀子; 木幡明子; 鳴海克哉; 田澤佑基; 吉山友二; 野田敏宏; 野田敏宏, 道薬誌, 28, 1, 2011年
- 表解注射薬の配合変化 ーThe change in combination of injection medicineー
北海道大学病院薬剤部
じほう, 2015年08月, 9784840747233, xv, 797p, 日本語, ［分担執筆］ - スポーツにおける薬物治療 : 処方と服薬指導
日本臨床スポーツ医学会学術委員会; 日本臨床スポーツ医学会; 北海道大学病院薬剤部
オーム社, 2014年12月, 9784274216893, viii, 349p, 日本語, ［分担執筆］
- シクロホスファミド関連心毒性の発現に及ぼす酸化還元酵素阻害薬の影響 ～JADER/FAERS解析～
石原孔明; 鳴海克哉; 上田一奈太; 岡本敬介; 小林正紀
第18回日本がん薬剤学会（JSOPP）学術大会, 2026年07月04日, ポスター発表
52032047 - シクロホスファミド誘発性心毒性における酸化還元酵素の関与 ―FAERS解析および基礎的検討―
石原孔明; 鳴海克哉; 上田一奈太; 岡本敬介; 小林正紀
医療薬学フォーラム2026／第34回クリニカルファーマシーシンポジウム, 2026年06月20日, ポスター発表
52032047 - クエチアピンによるAOX還元反応の阻害を介した薬物相互作用評価―基礎・疫学的アプローチによる検証―
鳴海克哉; 上田一奈太; 淺野秀峰; 岡本敬介; 小林正紀
第35回日本医療薬学会年会, 2025年11月23日, ポスター発表
2025年11月22日 - 2025年11月24日, 41929706 - HepG2細胞を用いたアルデヒドオキシダーゼ評価系の構築および エピジェネティック制御に関する考察
源尾有紗; 鳴海克哉; 淺野秀峰; 石原孔明; 上田一奈太; 岡本敬介; 小林正紀
第38回北海道薬物作用談話会, 2025年08月24日, 口頭発表（一般）
41929706 - 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
日本麻酔科学会第72回学術集会 【最優秀演題賞 受賞】, 2025年06月06日, 口頭発表（一般） - クエチアピンによるAOX介在性薬物相互作用メカニズムの解明
淺野秀峰; 上田一奈太; 鳴海克哉; 岡本敬介; 小林正紀
日本薬学会北海道支部第152回例会, 2025年05月17日, 日本語, 口頭発表（一般）
41929706 - HYA は1型糖尿病患者を模したモデルラットにおいて食後高血糖を改善 した。
山本悠太; 鳴海克哉; 山岸直子; 米島靖記; 井関健; 小林正紀; 金井克光
日本農芸化学会2025年度大会, 2025年03月06日, ポスター発表 - 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
第18回次世代を担う若手のための医療薬科学シンポジウム, 2024年10月03日, ポスター発表
41929706 - 消化管吸収モデルを用いたサケ白子抽出物由来デオキシリボヌクレオチドの小腸吸収動態評価
田口凜; 鳴海克哉; 佐藤浩志; 盛孝男; 岡本敬介; 古堅彩子; 小林正紀
第12回日本未病学会北海道支部会, 2024年09月16日, ポスター発表
46258738 - 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
第40回日本TDM学会・学術大会, 2024年07月15日, 口頭発表（一般）
41929706 - サケ白子抽出物に含まれるデオキシリボヌクレオチドの小腸吸収動態評価
田口凜; 鳴海克哉; 佐藤浩志; 盛孝男; 岡本敬介; 古堅彩子; 小林正紀
日本薬学会北海道支部第151回例会, 2024年07月06日, 口頭発表（一般）
46258738 - Oral administration of linoleic acid immediately before glucose load slowed the elevation of postprandial glucose levels via GPR120 pathway
Yuta Yamamoto; Katsuya Narumi; Naoko Yamagishi; Toshio Nishi; Takao Ito; Ken Iseki; Masaki Kobayashi; Yoshimitsu Kanai
第97回日本薬理学会年会, 2023年12月16日, 口頭発表（一般） - サケ白子抽出物による糖輸送担体の発現抑制機構
佐藤太一; 鳴海克哉; 佐藤浩志; 盛孝男; 古堅彩子; 小林正紀
第36回北海道薬物作用談話会, 2023年08月20日, 口頭発表（一般）
29449672;29449637 - 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2023 第31回クリニカルファーマシーシンポジウム, 2023年07月22日, ポスター発表
41929706;29449354;29449648 - Effect of aldehyde oxidase inhibitors on azathioprine-induced hematologic and hepatic injury
Hinata Ueda; Katsuya Narumi; Ayako Furugen; Masaki Kobayashi
日本薬学会第143年会―国際交流シンポジウム―, 2023年03月28日, 英語, ポスター発表
29449354 - Clinical importance of drug interaction between methotrexate and proton pump inhibitors and its potential mechanism
Katsuya Narumi
The 7th Japan-Taiwan Joint Symposium for Pharmaceutical Sciences, 2022年08月26日, 英語, シンポジウム・ワークショップパネル（指名）
29449354;29449648 - 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
第35回北海道薬物作用談話会, 2022年08月21日, 口頭発表（一般）
29449354 - 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
日本医療薬学会 第 5 回フレッシャーズ・カンファランス, 2022年06月12日, 口頭発表（一般）
29449354 - ER陽性乳がん細胞においてMCT1阻害剤はtamoxifenの生存率低下効果を増強する
灘井崇宜; 鳴海克哉; 古堅彩子; 井関健; 小林正紀
日本薬学会第142年会, 2022年03月27日, 口頭発表（一般）
29449355 - メトトレキサー トとプロトンポンプ阻害剤間の薬物相互作用に関する後方視的評価およびその相互作用機序の解析
鳴海克哉; 上田一奈太; 佐藤優; 古堅彩子; 井関健; 小林 正紀
第31回日本医療薬学会年会, 2021年10月09日, ポスター発表
29449354 - 濃縮型核酸輸送担体CNTsを介したデオキシリボヌクレオシド輸送の網羅的解析
山村泰輝; 鳴海克哉; 佐藤浩志; 盛孝男; 古堅彩子; 小林正紀
日本薬学会北海道支部第148回例会, 2021年05月22日, 口頭発表（一般）
29449637 - メトトレキサート投与時におけるプロトンポンプ阻害剤の in vivo および in vitro 薬物相互作用評価
上田一奈太; 鳴海克哉; 古堅彩子; 小林正紀; 井関健
日本薬学会北海道支部第147回例会（紙上開催）, 2020年05月23日, 口頭発表（一般）
29449648 - リンゴポリフェノールによるOATP2B1を介した薬物相互作用の解析
髙橋優花; 鳴海克哉; 古堅彩子; 小林正紀; 井関健
日本薬学会北海道支部第147回例会（紙上開催）, 2020年05月23日, 口頭発表（一般）
29449355 - dAMPの腸管吸収過程におけるCNT3およびCD73の協働的役割
大畑月香; 鳴海克哉; 佐藤浩志; 古堅彩子; 小林正紀; 井関健
日本薬学会第140年会（紙上開催）, 2020年03月25日, 口頭発表（一般）
29449355 - デオキシリボヌクレオチドの腸管吸収過程における CNT3およびCD73の協働的役割
大畑月香; 鳴海克哉; 佐藤浩志; 古堅彩子; 小林正紀; 井関健
第8回日本未病システム学会北海道支部会, 2019年10月27日, 口頭発表（一般） - NSAIDsによる小腸ペプチドトランスポーターを介した薬物間相互作用の解析
鎌田佑希; 鳴海克哉; 古堅彩子; 小林正紀; 井関健
第8回日本未病システム学会北海道支部会, 2019年10月27日, 口頭発表（一般）
29449514 - サケ白子に含まれるデオキシリボヌクレオチド類の消化管吸収機構
大畑月香; 鳴海克哉; 佐藤浩志; 古堅彩子; 小林正紀; 井関健
日本薬学会北海道支部第146回例会, 2019年05月18日, 口頭発表（一般）
29449355 - 紅茶成分によるBCRP介在性薬物相互作用の解析
奥原圭祐; 鳴海克哉; 近藤安佑子; 古堅彩子; 小林正紀; 井関健
第32回北海道薬物作用談話会, 2018年07月28日, 口頭発表（一般）
29449355 - Caco-2細胞におけるEGFR-TKIの輸送特性に関する研究
松谷竜之介; 鳴海克哉; 古堅彩子; 小林正紀; 井関健
第31回北海道薬物作用談話会, 2017年08月05日, 口頭発表（一般） - 高用量MTX投与時の血中MTX濃度に及ぼす胃酸分泌抑制剤の影響: hOAT3を介した薬物間相互作用
佐藤優; 鳴海克哉; 古堅彩子; 小林正紀; 井関健
日本薬学会北海道支部第144回例会, 2017年05月20日, 口頭発表（一般） - Theaflavin類の輸送におけるOATP2B1の寄与
近藤安佑子; 鳴海克哉; 小林拓; 古堅彩子; 小林正紀; 井関健
日本薬学会第137年会, 2017年03月27日, 口頭発表（一般） - サケ白子抽出物に含まれる核酸成分の消化管吸収に関する研究
鳴海克哉、堀内優一、佐藤浩志、小林正紀、井関健
第11回遺伝子栄養学研究会, 2016年09月09日, 口頭発表（一般） - 核酸製品の消化管吸収に関する研究
堀内優一; 鳴海克哉; 佐藤浩志; 小林正紀; 井関健
第30回北海道薬物作用談話会, 2016年07月31日, 口頭発表（一般） - アンチ・ドーピング領域における薬剤師の役割~大学教員の立場から~
鳴海克哉
第25回日本医療薬学会年会, 2015年11月21日, シンポジウム・ワークショップパネル（公募） - INVOLVEMENT OF MONOCARBOXYLATE TRANSPORTER IN THE UPTAKE OF LOXOPROFEN IN HUMAN INTESTINAL CACO-2 CELLS
Katsuya Narumi; Masaki Kobayashi; Ayako Furugen; Takehiro Yamada; Ken Iseki
第9回次世代を担う若手医療薬科学シンポジウム, 2015年11月07日, ポスター発表
29449357 - 血液内科病棟における薬剤師の役割 ～病院・大学兼務の立場から～
鳴海克哉
薬剤師ヘマトロジーフォーラム 札幌, 2014年11月27日, 公開講演，セミナー，チュートリアル，講習，講義等 - 高用量メトトレキサート(MTX)投与時の血中MTX濃度に及ぼす胃酸分泌抑制剤の影響
鳴海克哉、樋口一世、難波正志、山田順子、笠師久美子、山田武宏、豊嶋崇徳、井関健
第24回日本医療薬学会年会, 2014年09月28日, 口頭発表（一般） - 血液内科病棟における薬剤師の取り組み
鳴海克哉
Top Management Forum in Hokkaido, 2013年11月02日, 公開講演，セミナー，チュートリアル，講習，講義等
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- 臨床薬物動態解析演習, 2024年, 学士課程, 薬学部
- 病院実習, 2024年, 学士課程, 薬学部
- 救命救急実習, 2024年, 学士課程, 薬学部
- 薬物治療学Ⅰ, 2024年, 学士課程, 薬学部
- 実務実習事前実習, 2024年, 学士課程, 薬学部
- OSCE対応演習, 2024年, 学士課程, 薬学部
■ 共同研究・競争的資金等の研究課題
- AOX1の新規SNP機能解析および副作用予測因子としての薬物動態学的意義の検証
科学研究費助成事業 基盤研究(C)
2023年04月 - 2026年03月
鳴海 克哉
日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 23K06229 - サケ白子抽出物による腸管免疫賦活化作用および腸内細菌叢最適化への応用
2025年度学術奨励金
2025年07月
鳴海 克哉
一般財団法人東洋水産財団, 研究代表者 - メトトレキサートによる臓器障害を規定する薬物動態制御因子の薬理遺伝学的解析
科学研究費助成事業 基盤研究(C)
2020年04月 - 2023年03月
鳴海 克哉
本研究では、メトトレキサート(MTX)による副作用発現の個人差に焦点をあてその要因を明らかにすることを目的とした。これまでにヒト肝由来細胞株を用いた検討においてMTX誘発性肝障害は、アルデヒドオキシダーゼ1(AOX1)の機能低下により増強される可能性が示された。そこで、AOX1酵素活性の個人差を明らかにするため複数のデータベースよりアレル頻度の高いrSNPおよびcSNPを抽出し、各SNPの機能解析を行った。その結果、一つのcSNPにおいてAOX1ダイマー形成能の低下に伴う酵素活性の減少が認められた。したがって、このSNPがMTXを含むAOX1基質薬の治療効果または副作用発現に影響を及ぼす可能性が示された。
日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 20K07063 - 食品成分の動態学的特性に基づいた乳がん補完代替療法への応用
科学研究費助成事業 若手研究
2018年04月 - 2020年03月
鳴海 克哉
疫学調査や基礎研究により乳がんに対する食品成分の有用性が示唆されているが、その作用メカニズムに関しては明らかにされておらず、食品成分による乳がんの補完代替療法は実現していない。本研究では、乳がん細胞における膜タンパク質の機能に着目し、これらの膜タンパク質の活性に対する食品成分の阻害効果とがん細胞の生存・増殖との関連性を明らかにすることにより、乳がん補完代替療法としての食品成分の有用性を検証する。標的候補とした膜タンパク質に対する食品成分の阻害効果を検証するに先立ち、エストロゲン受容体(ER)陽性乳がん細胞株MCF-7およびT47Dを用いて、各膜タンパク質活性の阻害が乳がん細胞の生存・増殖に及ぼす影響を評価した。モノカルボン酸トランスポーター(MCT)1あるいはMCT4を特異的に阻害することにより乳がん細胞の生存率の低下が認められた。また、有機アニオン輸送ポリペプチド（OATPs）の阻害剤も同様に各乳がん細胞株の生存率を低下させた。しかしながら、これらの膜タンパク質の阻害により抗エストロゲン製剤であるタモキシフェン（4-OHT）に対する感受性は有意に低下した。さらに、4-OHTに対する感受性低下の要因として一部エストロゲンシグナルの増強が関わっている可能性が示された。したがって、ER陽性乳がんにおいて、細胞内外の乳酸やエストロゲン前駆体の輸送に関わる膜タンパク質の阻害は、ホルモン療法に対する耐性化を引き起こす可能性が示唆された。
日本学術振興会, 若手研究, 北海道大学, 研究代表者, 18K14416 - 慢性骨髄性白血病治療薬イマチニブの適正使用を目指した取り組み
科学研究費助成事業 奨励研究
2014年04月 - 2015年03月
鳴海 克哉
【研究目的】
イマチニブ(IMA)は慢性骨髄性白血病(CML)に用いられる分子標的治療薬である。近年、IMAの血中濃度(トラフ値)測定が保険診療で可能となったものの、副作用発現と血中濃度との関連性については明らかになっておらず、実際のCML診療において血中濃度測定はほとんど行われていない。そこで、北海道大学病院内においてIMAの血中濃度測定体制を構築し、CML診療におけるIMAの薬物治療モニタリング(TDM)を推進するとともに、血中濃度と副作用発現との関連性を明らかにするべく以下の検討を行った。
【研究方法・結果】
1. IMAの血中濃度測定系の構築
血中IMA濃度の測定は過去の報告(Miura et al. J Chromatogr Sci. 2011)を一部改変した方法を用い、HPLC法にて測定した。検量線は25-5000ng/mLの範囲で相関係数0.99以上の良好な直線性を示した。また、IMA服用患者(4名)の血中濃度を測定したところ、HPLC法とLC-MS/MS法(外部委託)による測定値には、良好な相関が認められ、本測定法が有用であることが確認された。
2. IMA服用患者におけるトラフ値と副作用発現に関する調査
北海道大学病院においてIMA服用患者(31例)を対象に、トラフ値四分位別(Q1-Q4)の有害事象発現率・グレードを調査したところ、Q4群(≧2033ng/mL)において赤血球減少、浮腫の発現率およびグレードが高い傾向が認められた。
【研究成果】
本研究では、IMAの血中濃度測定体制を構築し、院内におけるイマチニブの血中濃度を利用した治療マネージメントを可能にした。また、IMAのトラフ値上昇により、赤血球減少、浮腫などの副作用発現リスクが高まる可能性が示唆された。今後は症例数を追加し、さらなる解析が必要と考えられる。
日本学術振興会, 奨励研究, 北海道大学, 研究代表者, 26929020 - NSAIDsの消化管吸収に関する研究
科学研究費助成事業 奨励研究
2013年04月 - 2014年03月
鳴海 克哉
【研究目的】
NSAIDsは解熱鎮痛剤として広く使用されており、その中でも「ロキソプロフェン」は本邦において非常に汎用性の高い薬剤であり、国内初のスイッチOTCが上市された現在ではセルフメディケーションの観点からもその吸収動態を明らかにすることは重要である。本研究では、NSAIDsの適正使用をめざす一端として、ロキソプロフェンを中心としたNSAIDsの消化管吸収に着目し、その輸送機構を明らかにすべく種々検討を行った。
【研究方法】
消化管からのロキソプロフェンの輸送機構を評価するため、in vitro消化管吸収モデルであるCaco2細胞を用いて輸送実験を行い、以下の検討を行った。
①Caco-2細胞内へのロキソプロフェン輸送における濃度依存性、pH依存性を評価
②小腸上皮細胞に存在する各種トランスポーター(MCT, PEPT, OATP)の阻害剤および代表的なNSAIDsを用いてCaco-2細胞内へのロキソプロフェン輸送に対する阻害効果を評価
【研究結果】
①Caco-2細胞内へのロキソプロフェンの取り込みはFCCP(脱共役剤)共存下、4℃条件下において顕著に抑制された。また、その取り込みはpH依存性及び濃度依存性(飽和性)を示した。
②ロキソプロフェンの取り込みはMCTの阻害剤であるCHCにより阻害された。また、その取り込みはMCT (MCT1～4)の代表的基質である乳酸やサリチル酸、アセチルサリチル酸、ジクロフェナクなどのモノカルボン酸構造を有する化合物によって有意に阻害された。一方、PEPTおよびOATPファミリーの典型的基質であるGly-SarおよびE-3-Sはロキソプロフェンの輸送に対して阻害効果を示さなかった。
【研究成果】
本研究により、ロキソプロフェンの消化管吸収においてプロトン勾配を駆動力とするなんらかのトランスポーターが関与していることが明らかとなり、その輸送に関与するトランスポーターとしてMCTが寄与している可能性が強く示唆された。
日本学術振興会, 奨励研究, 北海道大学, 研究代表者, 25926011 - シクロホスファミド誘発性心毒性におけるアルデヒドオキ シダーゼの寄与と新規予防戦略への展開
2024年度 研究奨励金
鳴海 克哉
公益財団法人 臨床薬理研究振興財団, 研究代表者 - サケ白子を用いた難吸収性栄養素の腸管吸収促進への応用
２０２０年度「札幌ライフサイエンス産業活性化事業」 研究シーズ発掘補助金（札幌タレント補助金）
鳴海 克哉
公益財団法人北海道科学技術総合振興センター（ノーステック財団）, 研究代表者 - アファチニブの体内動態における薬物トランスポータの寄与と遺伝子多型情報に基づい た個別投与設計法の開発
平成３０年度 研究助成
鳴海 克哉
公益財団法人中冨健康科学振興財団, 研究代表者
- 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
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