Participation of OATP4C1 in the pharmacokinetics of drugs

• Project/Area Number: 18K06742
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Yamagata University (2019-2020); Tohoku University (2018)
• Principal Investigator: Yamaguchi Hiroaki 山形大学, 医学部, 教授 (80400373)
• Co-Investigator(Kenkyū-buntansha): 阿部 高明 東北大学, 医工学研究科, 教授 (80292209)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 腎排泄 / トランスポーター / 相互作用 / 薬物動態 / OATP4C1 / 薬物相互作用

Outline of Final Research Achievements

To clarify the pharmacokinetic importance of the organic anion transporter OATP4C1 in the renal excretion process of drugs, transport analysis using OATP4C1 stably expressing cells was conducted. The results showed that some HIV protease inhibitors, new quinolones, and remdesivir inhibited OATP4C1-mediated transport. Furthermore, ritonavir, levofloxacin, and remdesivir were found to be substrates of OATP4C1 transport, suggesting the involvement of OATP4C1 in the pharmacokinetics of these drugs, especially in the renal excretion process.

Academic Significance and Societal Importance of the Research Achievements

臨床における医薬品適正使用のためのエビデンスを構築するため、未だ情報が十分蓄積されているとはいえない腎臓特異的有機アニオントランスポーターOATP4C1について、その薬物動態学的重要性を明らかにすることを目的として研究を実施した。本研究では、OATP4C1の新たな輸送基質の発見ならびにOATP4C1を介した薬物間相互作用を引きおこす可能性がある薬物を同定することに成功した。

Research Products

• [Journal Article] Azelnidipine treatment reduces the expression of Cav1.2 protein (2021)
  • Author(s): Fumiaki Nasu, Yutaro Obara, Yosuke Okamoto, Hiroaki Yamaguchi, Kazuya Kurakami, Ikuo Norota, Kuniaki Ishi
  • Journal Title: Life Sciences Volume: 269 Pages: 119043-119043
  • DOI: 10.1016/j.lfs.2021.119043
  • Peer Reviewed / Open Access
• [Journal Article] Simultaneous analysis of drugs administered to lung-transplanted patients using liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring (2021)
  • Author(s): Shinya Takasaki, Tensei Hirasawa, Yu Sato, Masamitsu Maekawa, Taku Tsukamoto, Masafumi Kikuchi, Jiro Ogura, Yoshihiro Hayakawa, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Hiroaki Yamaguchi, Nariyasu Mano
  • Journal Title: Biomedical Chromatography Volume: 35 Issue: 6 Pages: 1-8
  • DOI: 10.1002/bmc.5067
  • Peer Reviewed
• [Journal Article] Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation (2020)
  • Author(s): Yabuki Hiroshi、Matsuda Yasushi、Watanabe Tatsuaki、Eba Shunsuke、Hoshi Fumihiko、Hirama Takashi、Oishi Hisashi、Sado Tetsu、Noda Masafumi、Sakurada Akira、Kikuchi Masafumi、Yamaguchi Hiroaki、Mano Nariyasu、Okada Yoshinori
  • Journal Title: Clinical Transplantation Volume: 34 Issue: 12 Pages: 1-9
  • DOI: 10.1111/ctr.14088
  • Peer Reviewed / Open Access
• [Journal Article] ATP-binding cassette transporter C4 is a prostaglandin D2 exporter in HMC-1 cells (2020)
  • Author(s): Nobuaki Tanaka, Junya Kawai, Noriyasu Hirasawa, Nariyasu Mano, Hiroaki Yamaguchi
  • Journal Title: Prostaglandins, Leukotrienes & Essential Fatty Acids Volume: 159 Pages: 102139-102139
  • DOI: 10.1016/j.plefa.2020.102139
  • Peer Reviewed
• [Journal Article] Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI?MS/MS (2020)
  • Author(s): Shigeta Kensuke、Kikuchi Masafumi、Tanaka Masaki、Takasaki Shinya、Oishi Hisashi、Sado Tetsu、Matsuda Yasushi、Noda Masafumi、Okada Yoshinori、Mano Nariyasu、Yamaguchi Hiroaki
  • Journal Title: Biomedical Chromatography Volume: 34 Issue: 8 Pages: 1-8
  • DOI: 10.1002/bmc.4853
  • Peer Reviewed / Open Access
• [Journal Article] Risk Factors for Severe Hyponatremia Related to Cisplatin: A Retrospective Case-Control Study (2019)
  • Author(s): Shiro Hatakeyama, Toshihiro Shida, Hiroaki Yamaguchi
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 11 Pages: 1891-1897
  • DOI: 10.1248/bpb.b19-00477
  • NAID: 130007740636
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-11-01
  • Peer Reviewed
• [Journal Article] Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients (2019)
  • Author(s): Masaki Tanaka, Masafumi Kikuchi, Shinya Takasaki, Tensei Hirasawa, Kensuke Shigeta, Aoi Noda, Miki Akiba, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
  • Journal Title: Journal of Pharmacy and Pharmaceutical Sciences Volume: 22 Pages: 407-417
  • DOI: 10.18433/jpps30505
  • Peer Reviewed
• [Journal Article] Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors (2019)
  • Author(s): Ichinose W, Cherepanov SM, Shabalova AA, Yokoyama S, Yuhi T, Yamaguchi H, Watanabe A, Yamamoto Y, Okamoto H, Horike S, Terakawa J, Daikoku T, Watanabe M, Mano N, Higashida H, Shuto S
  • Journal Title: J Med Chem Volume: - Issue: 7 Pages: 3297-3310
  • DOI: 10.1021/acs.jmedchem.8b01691
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease (2019)
  • Author(s): Kikuchi Koichi、Saigusa Daisuke、Kanemitsu Yoshitomi、Matsumoto Yotaro、Tsukamoto Hiroki、Abe Takaaki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1835-1835
  • DOI: 10.1038/s41467-019-09735-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of conjugated and unconjugated bile acid transport via human organic solute transporter α/β (2019)
  • Author(s): Suga Takahiro、Yamaguchi Hiroaki、Ogura Jiro、Mano Nariyasu
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Biomembranes Volume: 1861 Issue: 5 Pages: 1023-1029
  • DOI: 10.1016/j.bbamem.2019.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic performance evaluation of sulfate-conjugated cholesterol metabolites as urinary biomarkers of Niemann-Pick disease type C (2019)
  • Author(s): Masamitsu Maekawa, Aya Narita, Isamu Jinnoh, Takashi Iida, Thorsten Marquardt, Eugen Mengel, Yoshikatsu Eto, Peter T. Clayton, Hiroaki Yamaguchi, Nariyasu Mano
  • Journal Title: Clinica Chimica Acta Volume: 494 Pages: 58-63
  • DOI: 10.1016/j.cca.2019.03.1610
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis (2019)
  • Author(s): Takahiro Suga, Hiroaki Yamaguchi, Jiro Ogura, Saori Shoji, Masamitsu Maekawa, Nariyasu Mano
  • Journal Title: Toxicology and Applied Pharmacology Volume: 379 Pages: 114664-114664
  • DOI: 10.1016/j.taap.2019.114664
  • Peer Reviewed
• [Journal Article] Organogermanium suppresses cell death due to oxidative stress in normal human dermal fibroblasts (2019)
  • Author(s): Tomoya Takeda, Sota Doiyama, Junya Azumi, Yasuhiro Shimada, Yoshihiko Tokuji, Hiroaki Yamaguchi, Kosuke Nagata, Naoya Sakamoto, Hisashi Aso, Takashi Nakamura
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 13637-13637
  • DOI: 10.1038/s41598-019-49883-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Estimation of Blood Sirolimus Concentration Based on Tacrolimus Concentration/Dose Normalized by Body Weight Ratio in Lung Transplant Patients (2019)
  • Author(s): Masafumi Kikuchi, Kensuke Shigeta, Masaki Tanaka, Shinya Takasaki, Miki Akiba, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
  • Journal Title: Therapeutic Drug Monitoring Volume: 41 Issue: 5 Pages: 615-619
  • DOI: 10.1097/ftd.0000000000000649
  • Peer Reviewed
• [Journal Article] Involvement of H+-gradient dependent transporter in PGE2 release from A549 cells (2019)
  • Author(s): Nobuaki Tanaka, Hiroaki Yamaguchi, Nariyasu Mano
  • Journal Title: Prostaglandins Leukot Essent Fatty Acids Volume: 149 Pages: 30-36
  • DOI: 10.1016/j.plefa.2019.08.003
  • Peer Reviewed
• [Journal Article] Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann-Pick Disease Type C (2019)
  • Author(s): Masamitsu Maekawa, Isamu Jinnoh, Yotaro Matsumoto, Aya Narita, Ryuichi Mashima, Hidenori Takahashi, Anna Iwahori, Daisuke Saigusa, Kumiko Fujii, Ai Abe, Katsumi Higaki, Shosei Yamauchi, Yuji Ozeki, Peter T Clayton, Hiroaki Yamaguchi, Nariyasu Mano, et al.
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 20 Pages: 5018-5018
  • DOI: 10.3390/ijms20205018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of diagnostic performance of five urinary cholesterol metabolites for Niemann-Pick disease type C (2019)
  • Author(s): Masamitsu Maekawa, Isamu Jinnoh, Aya Narita, Takashi Iida, Daisuke Saigusa, Anna Iwahori, Hiroshi Nittono, Torayuki Okuyama, Yoshikatsu Eto, Kousaku Ohno, Peter T. Clayton, Hiroaki Yamaguchi, Nariyasu Mano
  • Journal Title: Journal of Lipid Research Volume: 60 Issue: 12 Pages: 2074-2081
  • DOI: 10.1194/jlr.m093971
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comprehensive and semi-quantitative analysis of carboxyl-containing metabolites related to gut microbiota on chronic kidney disease using 2-picolylamine isotopic labeling LC-MS/MS (2019)
  • Author(s): Kanemitsu Yoshitomi、Mishima Eikan、Maekawa Masamitsu、Matsumoto Yotaro、Saigusa Daisuke、Yamaguchi Hiroaki、Ogura Jiro、Tsukamoto Hiroki、Tomioka Yoshihisa、Abe Takaaki、Mano Nariyasu
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 19075-19075
  • DOI: 10.1038/s41598-019-55600-1
  • Peer Reviewed / Open Access
• [Journal Article] Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study (2019)
  • Author(s): Takasaki Shinya、Yamaguchi Hiroaki、Kawasaki Yoshihide、Kikuchi Masafumi、Tanaka Masaki、Ito Akihiro、Mano Nariyasu
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 5 Issue: 1 Pages: 6-6
  • DOI: 10.1186/s40780-019-0135-5
• [Journal Article] Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation (2018)
  • Author(s): Watanabe Takashi、Saito Takahiro、Rico Evelyn Marie Gutierrez、Hishinuma Eiji、Kumondai Masaki、Maekawa Masamitsu、Oda Akifumi、Saigusa Daisuke、Saito Sakae、Yasuda Jun、Nagasaki Masao、Minegishi Naoko、Yamamoto Masayuki、Yamaguchi Hiroaki、Mano Nariyasu、Hirasawa Noriyasu、Hiratsuka Masahiro
  • Journal Title: Biochemical Pharmacology Volume: 156 Pages: 420-430
  • DOI: 10.1016/j.bcp.2018.09.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals (2018)
  • Author(s): Hishinuma Eiji、Narita Yoko、Saito Sakae、Maekawa Masamitsu、Akai Fumika、Nakanishi Yuya、Yasuda Jun、Nagasaki Masao、Yamamoto Masayuki、Yamaguchi Hiroaki、Mano Nariyasu、Hirasawa Noriyasu、Hiratsuka Masahiro
  • Journal Title: Drug Metabolism and Disposition Volume: 46 Issue: 8 Pages: 1083-1090
  • DOI: 10.1124/dmd.118.081737
  • Peer Reviewed
• [Journal Article] Comparison of PETINIA and LC-MS/MS for determining plasma mycophenolic acid concentrations in Japanese lung transplant recipients (2018)
  • Author(s): Kikuchi Masafumi、Tanaka Masaki、Takasaki Shinya、Takahashi Akiko、Akiba Miki、Matsuda Yasushi、Noda Masafumi、Hisamichi Kanehiko、Yamaguchi Hiroaki、Okada Yoshinori、Mano Nariyasu
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 4 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s40780-018-0101-7
  • Peer Reviewed
• [Journal Article] Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics (2018)
  • Author(s): Kanaya Akihiro、Sato Toshihiro、Fuse Nobuo、Yamaguchi Hiroaki、Mano Nariyasu、Yamauchi Masanori
  • Journal Title: Journal of Anesthesia Volume: 32 Issue: 2 Pages: 236-243
  • DOI: 10.1007/s00540-018-2470-3
  • NAID: 40021526163
  • Peer Reviewed
• [Presentation] 手術不能または再発乳がんに対するCDK4/6阻害薬パルボシクリブの臨床判断分析を用いた臨床評価 (2021)
  • Author(s): 金子基子、志田敏宏、荒川一郎、澤田広樹、小倉次郎、山口浩明、井上忠夫
  • Organizer: 日本薬学会第141年会
• [Presentation] 新型コロナウイルス感染症治療薬レムデシビルおよびGS-441524の腎排泄および薬物相互作用におけるOATP4C1の役割 (2021)
  • Author(s): 佐藤紀宏、前川正充、阿部高明、山口浩明、眞野成康
  • Organizer: 日本薬学会第141年会
• [Presentation] 肺移植後患者における薬物療法個別化に向けて (2020)
  • Author(s): 山口浩明
  • Organizer: 日本病院薬剤師会東北ブロック第10回学術大会
• [Presentation] JADERを用いた白金系抗がん薬投与による低ナトリウム血症に関連した中枢神経症状の検討 (2020)
  • Author(s): 畠山史朗、加藤祐太、小原拓、志田敏宏、山口浩明
  • Organizer: 日本病院薬剤師会東北ブロック第10回学術大会
• [Presentation] ヘム生合成系初発酵素5-アミノレブリン酸合成酵素1(ALAS1)遺伝子破壊マウスにおけるグルコース刺激インスリン分泌異常 (2020)
  • Author(s): 武田和也、van Wilk Koen、木村朋寛、岡野聡、斉藤真一、山口浩明、児玉健、高橋研、田中徹、中島元夫、中島修
  • Organizer: 第93回日本生化学学会大会
• [Presentation] 経口がん分子標的薬の個別化投与設計に向けた取り組み (2019)
  • Author(s): 山口 浩明、髙﨑 新也、菊地 正史、川崎 芳英、伊藤 明宏、眞野 成康
  • Organizer: 日本薬剤学会第３４年会
• [Presentation] 急性薬毒物分析を保険診療の面から考える～現状と可能性～ (2019)
  • Author(s): 山口 浩明
  • Organizer: 第４１回日本中毒学会総会・学術集会
• [Presentation] ヒト血漿中脂肪酸ヒドロキシ化脂肪酸の定量法の開発 (2019)
  • Author(s): 山口 浩明、渡邉 亜侑、眞野 成康
  • Organizer: 第３０回日本臨床化学会東北支部総会
• [Presentation] イヌサフラン誤食によりコルヒチン中毒を発症した患者への薬剤師の関わり (2019)
  • Author(s): 矢内 一成、鈴木 博也、小林 正和、赤坂 和俊、山口 浩明、眞野 成康
  • Organizer: 第２９回日本医療薬学会年会
• [Presentation] Pharmacokinetic analysis based on clinical chemistry (2019)
  • Author(s): Hiroaki Yamaguchi
  • Organizer: The International Symposium of Health Care Technology, Drug Discovery and Chemical Biology 2019
  • Int'l Joint Research / Invited
• [Presentation] スニチニブのTDM普及に向けて (2019)
  • Author(s): 山口浩明、髙﨑新也、菊地正史、川崎芳英、荒井陽一、眞野成康
  • Organizer: 日本臨床腫瘍薬学会学術大会2019
• [Presentation] 臨床化学研究における質量分析の貢献 治療効果の最大化を目指した経口抗がん薬の治療薬物モニタリング (2018)
  • Author(s): 高崎新也、川崎芳英、菊地正史、田中雅樹、山口浩明、眞野成康
  • Organizer: 第43回日本医用マススペクトル学会年会
• [Presentation] トランスポーターを介した経口分子標的抗がん薬の相互作用 (2018)
  • Author(s): 山口浩明、眞野成康
  • Organizer: 第28回日本医療薬学会年会
• [Presentation] 東北病院薬剤師会員の学術研究に関する実態調査 (2018)
  • Author(s): 山口浩明、小林智徳、小原拓、赤嶺由美子、朝賀純一、芦埜和幸、 大原宏司、大村雅之、田村健悦、富岡佳久、豊口禎子、藤原洋之、 細井一広、渡辺剛
  • Organizer: 日本病院薬剤師会東北ブロック第8回学術大会
• [Remarks] 山形大学医学部附属病院薬剤部ホームページ
  • URL: https://www.yuhp-yaku.com/
• [Remarks] 山形大学医学部附属病院薬剤部ホームページ
  • URL: http://www.id.yamagata-u.ac.jp/Pharmacy/Pharm.html