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Molecular mechanism of non-linear first-pass metabolism

Research Project

Project/Area Number 03671043
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionChiba University

Principal Investigator

SUZUKI Tokuji  Chiba Univ., Dept.Biopharm., Prof., 薬学部, 教授 (40010219)

Co-Investigator(Kenkyū-buntansha) MASUBUCHI Yasuhiro  Chiba Univ., Dept.Biopharm., Res.Assoc., 薬学部, 助手 (10209455)
NARIMATSU Shizuo  Chiba Univ., Dept.Biopharm., Assoc.Prof., 薬学部, 助教授 (20113037)
Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1992: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsnon-linear first-pass metabolism / propranolol / bunitrolol / debrisoquine / Dark Agouti rat / P450BTL / genetic polymorphism / membrane transport / リドカイン / スダンIII / プロプラノロ-ル / ブニトロロ-ル
Research Abstract

The results described below are obtained for the molecular basis of first-pass effects using various techniques such as pharmaco- kinetics, enzyme kinetics, drug metabolism and molecular enzymology.
1. Involvement of high-affinity cytochrome P-450 isozymes in non- linear first-pass metabolism of drugs. The high-affinity P-450 isozymes which are defect in Dark Agouti strain rats were shown to be involved in the non-linear first-pass metabolism of propranolol (PL) and bunitrolol (BTL).
2. Purification of cytochrome P450 isozymes. A P450 isozyme (P450BTL) belonging to the CYP2D subfamily was purified from liver microsomes of Sprague-Dawley rats by pursuing the oxidation activity of BTL. Reconstitution and immunochemical studies indicated that this isozyme played major roles in hydroxylations of debrisoquine, BTL and PL in rat liver microsomes.
3. Mechanisms of first-pass effects of beta-blockers. In the isolated rat liver perfusion system, outflow PL concentrations were non-linearly increased against inflow PL concentrations. The metabolic rates observed in this system were predicted using the microsomal kinetic parameters, indicating the non-linear PL first-pass metabolism is due to the saturation of the reactions for the high-affinity enzymes engaging in PL ring hydroxylations.The mechanisms causing a difference between bioavailabilities of PL and BTL were studied in Wistar rats by the multiple indicator dilution technique. Kinetic analysis of the data obtained suggested that a difference not only in metabolic clearance but also in permeation clearance of each drug through cell membranes caused the difference between their bioavailabilities.

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Tokuji SUZUKI: "Impairment of bunitrolol 4-hydroxylase activity in liver microsomes of Dark Agouti rats" Biochemical Pharmacology. 42. 2241-2244 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tokuji SUZUKI: "Purification and characterization of a cytochrome P-450 isozyme catalyzing bunitrolol 4-hydroxylation in liver microsomes of male rats" Drug Metabolism and Disposition. 20. 367-373 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ryozo ISHIDA: "Induction of propranolol metabolism by the azo dye sudan III in rats" Biochemical Pharmacology. 43. 2489-2492 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ryozo ISHIDA: "Enzymatic basis for the nonlinearity of hepatic elimination of propranolol in the isolated perfused rat liver" Biochemical Pharmacology. 44. 2281-2288 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tokuji Suzuki: "Impairment of bunitrolol 4-hydroxylase activity in liver microsomes of Dark Agouti rats" Biochem. Pharmacol.42. 2241-2244 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tokuji Suzuki: "Purification and characterization of a cytochrome P-450 isozyme catalyzing bunitrolol 4-hydroxylation in liver microsomes of male rats" Drug Metab. Dispos.20. 367-373 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ryozo Ishida: "Induction of propranolol metabolism by the azo dye sudan III in rats" Biochem. Pharmacol.43. 2489-2492 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ryozo Ishida: "Enzymatic basis for the nonlinearity of hepatic elimination of propranolol in the isolated perfused rat liver" Biochem. Pharmacol.44. 2281-2288 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ryozo Ishida: "Induction of propranolol metabolism by the azo dye sudan 3 in rats" Biochemical Pharmacology. 43. 2489-2492 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Ryozo Ishida: "Enzymatic basis for the nonlinearity of hepatic elimination of propranolol in the isolated perfused rat liver" Biochemical Pharmacology. 44. 2281-2288 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tokuji Suzuki: "Impairment of bunitrolol 4ーhydroxylase activity in liver microsomes of Dark Agouti rats" Biochemical Pharmacology. 42. 2241-2244 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tokuji Suzuki: "Purification and characterization of a cytochrome Pー450 isozyme catalyzing bunitrolol 4ーhydroxylation in liver microsomes of male rats" Drug Metabolism and Disposition. (1992)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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