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Quantiative prediction of intestinal availability of CYP3A4 substrates

Research Project

Project/Area Number 17590135
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionKitasato University

Principal Investigator

ITOH Tomoo  Kitasato University, School of Pharmacy, Professor (30223168)

Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsfirst-pass effect / small intestine / CYP3A4 / human intestinal microsomes / Caco-2 cells
Research Abstract

Intestinal availability (Fg) of CYP3A4 substrates were quantitatively predicted based on the in vitro metabolic study with human intestinal microsomes and the efflux study with Caco-2 cells. Alprazolm (ALP), triazolam (TRZ), midazolam (MDZ), carbamazepine (CBZ) and testosterone (TST) were used as model CYP3A4 substrates. Fg values were predicted according to the single compartment kinetic model, and the more precise model was also developed which incorporated the transit of the drug in the intestinal lumen, absorption into the intestinal epithelial cells, the metabolism in the epithelial cells and the exit to the portal vein: Intestinal Transit, Absorption and Metabolism (ITAM) model.
Fg values of ALP, TRZ and CBZ were well predicted according to the single compartment kinetic model. However, the predicted Fg of MDZ was smaller than the reported Fg in humans. Since it has been reported that MDZ shows mechanism-based inhibitor like characteristics in CYP3A4 expression system, we studied if MDZ exhibits mechanism-based inhibitor like characteristics in human intestinal microsomes. MDZ did exhibit mechanism-based inhibitor like characteristics in human intestinal microsomes, and the Fg of MDZ was predicted using an ITAM model with mechanism based inhibitor like characteristics. The predicted Fg value of MDZ became close to the reported value, which indicated that MDZ acts as a mechanism-based inhibitor in the epithelial cells and that the metabolism of MDZ itself is inhibited in the process of absorption.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (19 results)

All 2007 2006 2005

All Journal Article (9 results) (of which Peer Reviewed: 2 results) Presentation (9 results) Book (1 results)

  • [Journal Article] Chiral recognition of amethopterin enantiomers by the reduced folate carrier in Caco-2 cells2007

    • Author(s)
      T. Narawa, Y. Tsuda, T. Itoh
    • Journal Title

      Drug Metab.Pharmacokinet. 22・1

      Pages: 33-40

    • NAID

      10018732926

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Chiral recognition of amethopterin enantiomers by the reduced folate carrier in Caco-2 cells.2007

    • Author(s)
      NarawaT., Tsuda Y., Itoh T.
    • Journal Title

      Drug Metab. Pharmacoldnet. 22(1)

      Pages: 33-40

    • NAID

      10018732926

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Chiral recognition of amethopterin enantiomers by the reduced folate carrier in Caco-2 cells.2007

    • Author(s)
      T.Narawa, Y.Tsuda, T.Itoh
    • Journal Title

      Drug Metab. Pharmacokinet. 22・1

      Pages: 33-40

    • NAID

      10018732926

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Prediction of intestinal first-oass effect based on a CAT model.2006

    • Author(s)
      M.Ishi.ii, Y.Iwase, T.Itoh
    • Journal Title

      JSSX Annual Meeting Abstracts.

      Pages: 237-237

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Quantitative prediction of human intestinal availability of CYP3A4 substrates based on unbound concentration.2006

    • Author(s)
      Y.Iwase, T.Itoh
    • Journal Title

      JSSX Annual Meeting Abstracts.

      Pages: 286-286

    • NAID

      130005442553

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Stereoselectivity of the reduced fblate carrier in Caco-2 cells2005

    • Author(s)
      T. Narawa, T. Itoh
    • Journal Title

      Chirality 17

      Pages: 444-449

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Stereoselectivity of the Reduced Folate Carrier in Caco-2 cells.2005

    • Author(s)
      Narawa T, Shimizu R, Takano S, Tsuda Y, Ono K, Ymada H, Itoh T
    • Journal Title

      Chirality 17(8)

      Pages: 444-449

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Stereoselectivity of the reduced folate carrier in Caco-2 cells.2005

    • Author(s)
      T.Narawa, T.Itoh
    • Journal Title

      Chirality 17

      Pages: 444-449

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Quantitative prediction of human intestinal availability of CYP3A4 substrates2005

    • Author(s)
      Y.Iwase, Y.Tsuda, T.Itoh
    • Journal Title

      JSSX-ISSX Joint Conference Abstracts

      Pages: 401-401

    • Related Report
      2005 Annual Research Report
  • [Presentation] Involvment of a calcium/calmodulin mediated pathway in the regulation of the transport activity of estrone-3-sulfate in Caco-2 cells.2006

    • Author(s)
      Takano S., Uchida M., Itoh T.
    • Organizer
      21st JSSX Annual Meeting
    • Place of Presentation
      Tokyo
    • Year and Date
      2006-12-01
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Regulation of OATP2B1(OATP-B) activity by signal transduction pathways.2006

    • Author(s)
      Uchida M., Takano S., Itoh T.
    • Organizer
      21st JSSX Annual Meeting
    • Place of Presentation
      Tokyo
    • Year and Date
      2006-12-01
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Prediction of intestinal first-pass effect based on a CAT model2006

    • Author(s)
      M. Ishiji, Y. Iwase, T. Itoh
    • Organizer
      21st JSSX Annual Meeting[Abstract p.237]
    • Place of Presentation
      Tokyo
    • Year and Date
      2006-11-30
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Prediction of intestinal first-pass effect based on a CAT model.2006

    • Author(s)
      Ishiji M., Iwase Y. and Itoh T.
    • Organizer
      21st JSSX Annual Meeting
    • Place of Presentation
      Tokyo
    • Year and Date
      2006-11-30
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] INDUCTION OF CYP3A BY DEXAMETHASONE IN RAT SMALL INTESTINE AND LIVER.2006

    • Author(s)
      Saitoh M., Ohsawa M., Takano S., Tsuda Y., Itoh T.
    • Organizer
      21st JSSX Annual Meeting
    • Place of Presentation
      Tokyo
    • Year and Date
      2006-11-29
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Quantitative prediction of human intestinal availability of CYP3A4 substrates based on unbound concentration.2006

    • Author(s)
      Iwase Y., Isiji M., Narawa T., Tsuda Y., Itoh T.
    • Organizer
      21st JSSX Annual Meeting
    • Place of Presentation
      Tokyo
    • Year and Date
      2006-11-29
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Stereoselective Transport of Reduced Folate Carrier 12005

    • Author(s)
      Narawa T, Takano S, Tsuda Y, Itoh T
    • Organizer
      13th NA ISSX/20th JSSX Meeting
    • Place of Presentation
      Maui, U.S.A
    • Year and Date
      2005-11-26
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Quantitative Prediction of Human Intestinal Availability of CYP3A4 Substrates2005

    • Author(s)
      Iwase Y, Tsuda Y, Itoh T
    • Organizer
      13th NA ISSX/20th JSSX Meeting
    • Place of Presentation
      Maui, U.S.A
    • Year and Date
      2005-10-27
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Regulation of PEPT1 Activity by Protein Kinase C2005

    • Author(s)
      Takano S, Itoh T
    • Organizer
      13th NA ISSX/20th JSSX Meeting
    • Place of Presentation
      Maui, U.S.A
    • Year and Date
      2005-10-26
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] パートナー薬剤学2007

    • Author(s)
      伊藤 智夫
    • Total Pages
      30
    • Publisher
      南江堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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