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Development of the prediction method for pharmacokinetics using biomarkers for drug transports and metabolisms

Research Project

Project/Area Number 17K15536
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionYokohama College of Pharmacy

Principal Investigator

Yoshikado Takashi  横浜薬科大学, 薬学部, 講師 (70535096)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords薬物相互作用 / トランスポーター / 基質薬・阻害薬 / 内在性基質 / バイオマーカー / 生理学的薬物速度論モデル / コプロポルフィリン / 薬物間相互作用 / OATP1Bs / PBPKモデル / 薬物動態学
Outline of Final Research Achievements

The aim of the present study was to establish a physiologically-based pharmacokinetic model for coproporphyrin I (CP-I), a biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1Bs (OATP1Bs), using clinical DDI data with an OATP1Bs inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (Ki,u,OATP1Bs) and multidrug resistance-associated protein 2-mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively. Ki,u,OATP1Bs values optimized by nonlinear least-squares fitting were ~0.5-fold of the initial value. It was determined that the blood concentration-time profiles of four statins were well-predicted using corrected individual Ki,u,OATP1B values (ratio of in vitro Ki,u(statin)/ in vitro Ki,u(CP-I)). In conclusion, PBPK modeling of CP-I supports dynamic prediction of OATP1Bs-mediated DDIs.

Academic Significance and Societal Importance of the Research Achievements

本研究により、OATP1B内在性基質のCP-Iをバイオマーカーとして用いた薬物相互作用予測法を開発したことで、創薬および臨床の両方に貢献することができる。創薬においては、バイオマーカーを測定することにより、医薬品候補化合物のOATP1Bへの影響について、プローブ薬を投与することなく予測することができるようになる。これは新薬開発における臨床試験にバイオマーカー測定系を導入することで可能となることから、大幅なコスト削減に繋がる。また臨床においては、患者のバイオマーカーを測定することにより、OATP1B基質となる医薬品の体内動態の個人差を、投与前に予測することが可能になると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (11 results)

All 2019 2018 2017

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results)

  • [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.
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: 34 Issue: 1 Pages: 78-86

    • DOI

      10.1016/j.dmpk.2018.09.003

    • NAID

      50014558502

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3.2018

    • Author(s)
      Yoshikado T., Toshimoto K., Maeda K., Kusuhara H., Kimoto E., Rodrigues AD., Chiba K., Sugiyama Y.
    • Journal Title

      CPT Pharmacometrics Syst Pharmacol.

      Volume: 7 Issue: 11 Pages: 739-747

    • DOI

      10.1002/psp4.12348

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers.2018

    • Author(s)
      Takehara I, Yoshikado T, Ishigame K, Mori D, Furihata KI, Watanabe N, Ando O, Maeda K, Sugiyama Y, Kusuhara H.
    • Journal Title

      Pharmaceutical Research

      Volume: 35 Issue: 7 Pages: 138-138

    • DOI

      10.1007/s11095-018-2416-3

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 肝トランスポーターを介したDDIの内在性バイオマーカーに基づく予測2019

    • Author(s)
      吉門 崇
    • Organizer
      第29回日本医療薬学会年会 福岡
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] OATP1B内在性基質コプロポルフィリンIの生理学的薬物速度論モデルを用いた薬物間相互作用予測法の提唱2019

    • Author(s)
      吉門 崇、年本 広太、前田 和哉、楠原 洋之、千葉 康司、杉山 雄一
    • Organizer
      日本薬剤学会第34年会 富山
    • Related Report
      2019 Annual Research Report
  • [Presentation] OATP1B内在性基質のコプロポルフィリンIをバイオマーカーとして用いた薬物間相互作用の予測2019

    • Author(s)
      吉門 崇、年本 広太、前田 和哉、楠原 洋之、千葉 康司、杉山 雄一
    • Organizer
      第41回生体膜と薬物の相互作用シンポジウム 千葉
    • Related Report
      2019 Annual Research Report
  • [Presentation] Proposal for predicting drug-drug interactions using a PBPK model of coproporphyrin I as an endogenous OATP1B biomarker2018

    • Author(s)
      吉門崇
    • Organizer
      日本薬物動態学会第33回年会/MDO国際合同学会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 臨床ステージで行う内在性バイオマーカーに基づくDDIリスク評価 -肝トランスポーターを中心に-2018

    • Author(s)
      吉門崇
    • Organizer
      CBI学会第400研究講演会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Construction of a physiologically-based pharmacokinetic model of coproporphyrin I, a putative endogenous probe for hepatic OATP1Bs and MRP22018

    • Author(s)
      Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Chiba K, Sugiyama Y
    • Organizer
      第39回日本臨床薬理学会学術総会/第18回国際薬理学・臨床薬理学会議
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 生理学的薬物速度論モデルを用いたOATP1BsおよびMRP2内在性基質コプロポルフィリンIの体内動態解析2018

    • Author(s)
      吉門崇、年本広太、前田和哉、楠原洋之、千葉康司、杉山雄一
    • Organizer
      日本薬剤学会第33年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Construction of a physiologically-based pharmacokinetic model for coproporphyrin I, an endogenous probe for hepatic organic anion transporting polypeptides (OATPs)2017

    • Author(s)
      Takashi Yoshikado, Kazuya Maeda, Hiroyuki Kusuhara, Koji Chiba, and Yuichi Sugiyama
    • Organizer
      32nd JSSX Annual Meeting (Tokyo, Japan)
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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