Exploration study to identify pharmacokinetic biomarkers by pharmacometabolomic approaches
| Project/Area Number |
17H04100
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Kusuhara Hiroyuki 東京大学, 大学院薬学系研究科(薬学部), 教授 (00302612)
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| Co-Investigator(Kenkyū-buntansha) |
藤田 健一 昭和大学, 薬学部, 教授 (60281820)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | バイオマーカー / 内在性基質 / 薬物トランスポーター / 個体間変動 / 薬物相互作用 / 一塩基多型 / ファーマコメタボローム / 内在性バイオマーカー / ファーマコメタボロミクス / 体内動態 / 薬剤応答性 / 代謝物 / 薬物動態学 / 薬物間相互作用 |
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| Outline of Final Research Achievements |
Endogenous biomarkers are considered important in drug development to advance transporter-mediated drug-drug interaction (DDI) risk assessment. Drug interaction studies with OATP1B inhibitors and OAT inhibitors that caused transporter-mediated drug interactions identified metabolites and their pharmacokinetic parameters associated with transporter activities. Based on a genome-wide association analysis of serum metabolite profiles, a metabolite was selected as candidate OCT2 biomarker which was supported by non-clinical studies on renal organic cation transporters. We obtained information on transcriptional regulation as a underlying mechanism by which polymorphisms affect OCT2 expression. In the samples administered with irinotecan, the biomarkers were quantified which help understanding the relationship with the transporter activities and interindividual difference in the plasma concentrations of irinotecan and its active metabolites.
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| Academic Significance and Societal Importance of the Research Achievements |
薬物動態の個体間変動は個体の薬剤応答の個体間変動を規定する因子である。その1つである薬物相互作用は新薬開発において必ず評価される項目であるが、現行の予測方法では偽陰性/偽陰性を生じ得る。本研究では薬物トランスポーターの内在性代謝物と、そのトランスポーター感受性を見出した。当該化合物はバイオマーカーとして利用可能であり、現行の方法の問題点を克服する手法の1つとして、産業界・規制当局から期待されている。また、内在性代謝物に注目することで、大規模データから薬物動態関連因子であるトランスポーターの機能に関連する遺伝子変異を抽出することが可能であり、新たな個体間変動要因を解明することに繋がると考える。
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Report
(4 results)
Research Products
(52 results)
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[Journal Article] Alteration in the Plasma Concentrations of Endogenous Organic Anion-Transporting Polypeptide 1B Biomarkers in Patients With Non-Small Cell Lung Cancer Treated With Paclitaxel2020
Author(s)
Mori D, Ishida H, Mizuno T, Kusumoto S, Kondo Y, Izumi S, Nakata G, Nozaki Y, Maeda K, Sasaki Y, Fujita KI, Kusuhara H.
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Journal Title
Drug Metab Dispos
Volume: 48
Issue: 5
Pages: 387-394
DOI
Related Report
Peer Reviewed
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[Journal Article] Dose-Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs.2020
Author(s)
Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M, David Rodrigues A, Muto C, Furihata K, Sugiyama Y, Kusuhara H
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Journal Title
Clin Pharmacol Ther
Volume: 107
Issue: 4
Pages: 1004-1013
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Elucidation of N 1-methyladenosine as a Potential Surrogate Biomarker for Drug Interaction Studies Involving Renal Organic Cation Transporters2019
Author(s)
Miyake T, Mizuno T, Takehara I, Mochizuki T, Kimura M, Matsuki S, Irie S, Watanabe N, Kato Y, Ieiri I, Maeda K, Ando O, Kusuhara H.
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Journal Title
Drug Metab Dispos
Volume: 47
Issue: 11
Pages: 1270-1280
DOI
Related Report
Peer Reviewed
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[Journal Article] Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers.2019
Author(s)
Mori D, Kashihara Y, Yoshikado T, Kimura M, Hirota T, Matsuki S, Maeda K, Irie S, Ieiri I, Sugiyama Y, Kusuhara H.
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Journal Title
Drug Metab Pharmacokinet
Volume: 34
Issue: 1
Pages: 78-86
DOI
NAID
Related Report
Peer Reviewed
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[Journal Article] Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium2018
Author(s)
Chu X, Liao M, Shen H, Yoshida K, Zur AA, Arya V, Galetin A, Giacomini KM, Hanna I, Kusuhara H, Lai Y, Rodrigues D, Sugiyama Y, Zamek-Gliszczynski MJ, Zhang L; International Transporter Consortium.
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Journal Title
Clin Pharmacol Ther
Volume: 104
Issue: 5
Pages: 836-864
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Comprehensive comparison of the effect of three doses of an OATP1B inhibitor, rifampicin, on the plasma concentrations of twenty-eight endogenous compounds in healthy volunteers2019
Author(s)
Hiroyuki Kusuhara,Daiki Mori, Emi Kimoto, Brian Rago, Yusuke Kondo, Amanda King-Ahmad, Ragu Ramanathan, Linda S. Wood, Jillian G. Johnson, Vu H. Le, Manoli Vourvahis, A. David Rodrigues, Chieko Muto, Kenichi Furihata, Yuichi Sugiyama
Organizer
日本薬物動態学会第34回年会
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[Presentation] Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs2018
Author(s)
Daiki Mori, Yushi Kashihara, Takashi Yoshikado, Miyuki Kimura, Takeshi Hirota, Shunji Matsuki, Kazuya Maeda, Shin Irie, Ichiro Ieiri, Yuichi Sugiyama, Hiroyuki Kusuhara
Organizer
日本薬物動態学会 第33回年会/MDO 国際合同学会
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