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Application of Sandwich-cultured hepatocytes for analysis of drug-drug interaction on bile canalicular transporters

Research Project

Project/Area Number 23659076
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionKanazawa University

Principal Investigator

TAMAI Ikumi  金沢大学, 薬学系, 教授 (20155237)

Co-Investigator(Kenkyū-buntansha) NAKANISHI Takeo  金沢大学, 薬学系, 准教授 (30541742)
KUNISHIMA Munetaka  金沢大学, 薬学系, 教授 (10214975)
Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords輸送体 / 肝細胞 / 薬物間相互作用 / 副作用 / 胆汁排泄 / 可視化 / 薬物誘導性肝障害 / MRP2
Research Abstract

Interplay of transporters and enzymes is essential to understand drug disposition in tissues such as liver and intestine. When we consider drug-drug interaction (DDI) on liver bile canalicular transporters,metabolites formed in the hepatocytes must be considered, since many of conjugated metabolites show higher affinity to those transporters like MRP2. We established a quantitative time-lapse imaging-based analysis (QTLI) to assess Mrp2-mediated DDIs in sandwich-cultured hepatocytes (SCHs), utilizing fluorescent probe substrate of MRP2, (5,6)-carboxy-2’,7’-dichlorofluorescein (CDF). When estradiol (E2) was chosen as affecting compound, its metabolite estradiol-17β-glucuronide (E17G) but not E2 itself was confirmed to inhibit Mrp2-mediated CDF transport. When SCRHs were preincubated with E2, fluorescence accumulated in bile canaliculi formed in SCRH was decreased depending upon both length of preincubation period and concentration of E2 given in extracellular medium. The decrease in accumulated fluorescence agreed with an increase in intracellular concentration of E17G generated in hepatocytes, suggesting that the phase II biotransformation is mirrored in MRP2-mediated transport by QTLI. Since SCHs well maintain hepatic uptake transport activity, intracellular binding and drug metabolizing activity as in vitro system, QTLI in SCHs provides a convenient platform to develop an evaluation system for transporter-based DDIs without identifying metabolites of drug candidates.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (11 results)

All 2012 2011 Other

All Journal Article (3 results) (of which Peer Reviewed: 2 results) Presentation (6 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Application ofquantitative time-lapse imaging(QTLI) for evaluation of Mrp2-baseddrug-drug interaction induced byliver metabolites.2012

    • Author(s)
      Nakanishi T, Ikenaga M, Fukuda H, Matsunaga N, Tamai I
    • Journal Title

      Toxicol ApplPharmacol

      Volume: 263(2) Pages: 244-50

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Application of quantitative time-lapse imaging (QTLI) for evaluation of Mrp2-based drug-drug interaction induced by liver metabolites.2012

    • Author(s)
      Nakanishi T, Ikenaga M, Fukuda H, Matsunaga N, Tamai I.
    • Journal Title

      Toxicology and Applied Pharmacology

      Volume: 263 Pages: 244-250

    • Related Report
      2012 Annual Research Report
  • [Journal Article] Quantitative time-lapse imaging (QTLI)-based analysis of drug-drug interaction mediated by . hepatobiliary transporter, multidrug associated protein 2, in sandwich-cultured rat hepatocytes2011

    • Author(s)
      Nakanishi T., Shibue Y., Fukuyama Y., Yoshida K., Fukuda H., Shirasaka Y., Tamai I
    • Journal Title

      Drug Metab. Dispos

      Volume: 39(6) Issue: 6 Pages: 984-991

    • DOI

      10.1124/dmd.111.038059

    • Related Report
      2012 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Presentation] Interplay and difference of transporters and enzymes in drug absorption, disposition and action2012

    • Author(s)
      Ikumi Tamai
    • Organizer
      50thAnniversary Symposium on Cytochrome P450 in Fukuoka
    • Place of Presentation
      Kyushu University, Fukuoka, Japan.
    • Year and Date
      2012-12-02
    • Related Report
      2012 Final Research Report
  • [Presentation] Application ofquantitative time-lapse imaging (QTLI)for evaluation of MRP2/MRP2-baseddrug-drug interaction in rat andhuman hepatocytes2012

    • Author(s)
      Ikumi Tamai
    • Organizer
      The 27thJSSX Annual Meeting
    • Place of Presentation
      タワーホール船堀,東京
    • Year and Date
      2012-11-20
    • Related Report
      2012 Final Research Report
  • [Presentation] Analysis of Drug Interaction on Bile Canalicular Transporters. International Symposium on PPF Molecular Pharmacokinetics2012

    • Author(s)
      Ikumi Tamai
    • Place of Presentation
      Hitotsubashi-Hall, Tokyo, Japan
    • Year and Date
      2012-01-17
    • Related Report
      2012 Final Research Report
  • [Presentation] In vitro蛍光イメージング(QTL1)法を用いたMRP2機能変動評価-肝代謝を考慮した薬物間相互作用予測への応用-2011

    • Author(s)
      Ikumi Tamai
    • Organizer
      日本薬学会北陸支部第123回例会
    • Place of Presentation
      金沢大学(石川県)
    • Year and Date
      2011-11-27
    • Related Report
      2012 Final Research Report
  • [Presentation] In vitro蛍光イメージング(QTLI)法を用いたMRP2機能変動評価 -肝代謝を考慮した薬物間相互作用予測への応用-2011

    • Author(s)
      池永美穂、中西猛夫、福田 元、白坂善之、玉井郁巳
    • Organizer
      日本薬学会北支部第123回例会
    • Place of Presentation
      金沢大学
    • Related Report
      2011 Research-status Report
  • [Presentation] Application of quantitative time-laspe imaging(QTL1) for evaluation of MRP2/MRP2-based drug-drug interaction in rat and human hepatocytes.

    • Author(s)
      池永美穂、、中西猛夫、福田元、松永憲和、玉井郁巳
    • Organizer
      The 27th JSSX Annual Meeting
    • Place of Presentation
      タワーホール船堀(東京都)
    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.p.kanazawa-u.ac.jp/lab/doutai.html

    • Related Report
      2012 Final Research Report
  • [Patent(Industrial Property Rights)] 分子イメージングにより代謝機能を測定するための検査薬2012

    • Inventor(s)
      川井恵一、玉井郁巳、国嶋崇隆太、中西猛夫、小林正和
    • Industrial Property Rights Holder
      金沢大学
    • Industrial Property Number
      2012-044231
    • Filing Date
      2012-02-29
    • Related Report
      2012 Final Research Report

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Published: 2011-08-05   Modified: 2019-07-29  

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