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Interplay between in tasting and liver for the first-pass metabolism of orally administered drugs

Research Project

Project/Area Number 13672384
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionTOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY

Principal Investigator

HASHIMOTO Yukiya  Toyama Medical and Pharmaceutical University Graduate School of Pharmaceutical Sciences Professor, 大学院・薬学研究科, 教授 (90228429)

Co-Investigator(Kenkyū-buntansha) TAGUCHI Masato  Toyama Medical and Pharmaceutical University Graduate School of Pharmaceutical Sciences Instructor, 大学院・薬学研究科, 助手 (20324056)
AIBA Tetsuya  Toyama Medical and Pharmaceutical University Graduate School of Pharmaceutical Sciences Associate Professor, 大学院・薬学研究科, 助教授 (00231754)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
Keywordsbioavailability / tacrolimus / propranolol / renal failure / CYP3A / intestinal metabolism / first-pass effect / ajmaline / タクロスリム / 小腸 / 初回通過効果 / CYP3A4 / トランスポータ / P-糖蛋白質 / CYP2D6
Research Abstract

Tacrolimus has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. The rate of absorption of tacrolimus in the intestine was rapid, and the drug was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 26% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver, and that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration. Furthermore, the effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in cisplatin-induced renal failure model rats. The bioavailability of tacrolimus was increased by 35% in rats with impaired renal function as compared with normal control. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine in rats with renal failure. These results suggested that the hepatic metabolism of tacrolimus is impared in rats with renal failure, and that the accelerated absorption rate in the intestine in renal failure is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Hashimoto, Yukiya: "Effect of experimental renal dysfunction on bioavailability of ajmaline in rats"J. Pharm. Pharmacol.. 53. 805-813 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuo, Yumiko: "Transport of levofloxacin in the OK kidney epithelial cell line : interaction with P-amino hippurate transport"Pharm. Res.. 18. 573-578 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okabe, Hiromi: "Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction"J. Pharm. Pharmacol.. 54. 65-70 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shiiki, Takeshi: "Simulation for population pharmacodynamic analysis of dose-ranging trials"Pharm. Res.. 19. 909-913 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Habu, Yasuhi: "p-Aminohippurate transport at the apical membrane in the OK kidney epithelial cell line"Pharm. Res.. 19. 1822-1826 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto, Yukiya et al.: "Effect of experimental renal dysfunction on bioavailability of ajmaline in rats."J. Pharm. Pharmacol.. 53-6. 805-813 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuo, Yumiko et al.: "Transport of levofloxacin in the OK kidney epithelialcell line : interaction with p-aminohippurate transport."Pharm. Res.. 18-5. 573-578 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okabe, Hiromi et al.: "Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction."J. Pharm. Pharmacol.. 54-1. 65-70 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shiiki, Takeshi et al.: "Simulation for population pharmacodynamic analysis of dose-ranging trials : usefulness of the mixture model analysis for detecting nonresponders."Pharm. Res.. 19-6. 909-913 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Habu, Yasushi et al.: "p-Aminohippurate transport at the apical membrane in the OK kidney epithelial cell line."Pharm. Res.. 19-12. 1822-1826 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okabe, Hiromi: "Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction"J. Pharm. Pharmacol.. 54・1. 65-70 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shiiki, Takeshi: "Simulation for population pharmacodynamic analysis of doseranging trials"Pharm. Res.. 19・6. 909-913 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Habu, Yasushi: "p-Aminohippurate Transport at the apical membrane in the OK kidney epiothelial cell line"Pharm. Res.. 19・12. 1822-1826 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsuo, Yumiko et al.: "Transport of levofloxacin in the OK kidney epithelial cell line : interaction with p-aminohipurate transport"Pharm. Res.. 18・5. 573-578 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yukiya, Hashimoto: "Effect of experimental renal dysfunction on bioavailability of ajimaline in rats"J. Pharm. Pharmacol.. 53・6. 805-813 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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