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Population Analysis of Pharmacokinetics and Pharmacodynamics of an Immunosuppresive Agent

Research Project

Project/Area Number 06672140
Research Category

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

Allocation TypeSingle-year Grants
Research Field Physical pharmacy
Research InstitutionTokyo Medical and Dental University (1995)
Kyoto University (1994)

Principal Investigator

YASUHARA Masato  Tokyo Medical & Dental Univ., Med., Prof., 医学部, 教授 (00127151)

Co-Investigator(Kenkyū-buntansha) HASHIMOTO Yukiya  Kyoto Univ., Med., Lecturer, 医学部, 講師 (90228429)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1994: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsImmunosuppressive agent / Population analysis / Tacrolimus / Pharmacokinetics / Pharmacodynamics / Hepatic extraction / Living-related donor liver transplantation / 肝疾患
Research Abstract

The establishment of reliable postoperative immunosuppressive therapy is essential to improve the outcome of organ transplantation. We have investigated the pharmacokinetics and pharmacodynamics of tacrolimus (FK506), a new immunosuppressive agent, in patients receiving living-related donor liver transplantations (LRLT) at the Second Department of Surgery, Kyoto University Hospital.
1.Of the 55 patients receiving LRLT,6 had and episode of hepatic dysfunction, which was suspected to the liver allograft rejection. The onset of rejection was associated with lower blood concentration of tacrolimus. On the other hand, most of the adverse effects, such as hyperkalemia, renal dysfunction and hyperglycemia, occurred at the blood concentration higher than 20 ng/ml. Thus, the therapeutic effect and toxicity of tacrolimus were related to trough blood concentrations and the therapeutic blood concentration of tacrolimus ranged from nearly 10 to 20 ng/ml for impatients after LRLT.
3.The pharmacokinetics of tacrolimus after i.v.infusion and oral administration was analyzed with an one-compartment model using the NONMEM program developed for population analysis. NONMEM analysis showed that the clearance of tacrolimus was related to body weight and days after operation and that the availability was about 19%.
3.The careful dose adjustment based on TDM is essential because of the large inter-and intra-individual variability in the pharmacokinetics of tacrolimus.
4.The animal experiment indicated that the clearance and hepatic extraction of tacrolimus reduced significantly in rats with hepatic dysfunction.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Y. Hashimoto: "Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients" Biol. Pharm. Bull.17. 323-326 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M. Takano: "Transport of gentamicin and fluid-phase endocytosis markers in the LLC-PK1 kidney epithelial cell line" J. Pharmacol. Exp. Ther.268. 669-674 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M. Yasuhara: "Natriuretic peptide-potentiating actions of neutral endopeptidase inhibition in rats with experimental heart failure" Pharm. Res.11. 1726-1730 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M. Yasuhara: "Pharmacokinetics and pharmacodynamics of FK506 in pediatric patients receiving living related donor liver transplantations" Transplant. Proc.27. 1108-1110 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M. Hirai: "Cepharanthin, a multidrug resistant modifier, is a substrate for P-glycoprotein" J. Pharmacol. Exp. Ther.275. 73-78 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Hashimoto: "Simulation for population analysis of Michaelis-Menten elimination kinetics" J. Pharmacokin. Biopharm.23. 205-216 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Hashimoto: "Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients" Biol.Pharm.Bull.17. 323-326 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Takano: "Transport of gentamicin and fluid-phase endo-cytosis markers in the LLC-PK1 kidney epithelial cell line" J.Pharmacol.Exp.Ther.268. 669-674 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Yasuhara: "Natriuretic peptide-potentiating actions of neutral endopeptidase inhibition in rats with experimental heart failure" Pharm.Res.11. 1726-1730 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Yasuhara: "Pharmacokineics and pharmacodynamics of FK506 in pediatric patients receiving living related donor liver transplantations" Transplant.Proc.27. 1108-1110 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Hirai: "Cepharanthin, a multidrug resistant modifier, is a substrate for p-glycoprotein" J.Pharmacol.Exp.Ther.275. 73-78 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Hashimoto: "Simulation for population analysis of Michaelis-Menten elimination kinetics" J.Pharmacokin.Biopharm.23. 205-216 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Tomita: "Transport of oral cephalosporins by the H+/dipeptide cotransporter and distribution of the transport activity in isolated rabbit intestinal epithelial cells." J.Pharmacol.Exp.Ther.272. 63-69 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] M.Yasuhara: "Pharmacokinetics and pharmacodynamics of FK506 in pediatric patients receiving living related donor liver transplantations" Transplantation Proc.27. 1108-1110 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] M.Hirai: "Cepharanthin,a multidrug resistant modifier,is a substrate for P-glycoprotein" J.Pharmacol.Exp.Ther.275. 73-78 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y.Hashimoto: "Simulation for population analysis of Michaelis-Menten elimination kinetics" J.Pharmacokin.Biopharm.23. 205-216 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 橋田,亨: "マイクロパーティクルEIA法によるタクロリムスの血中濃度モニタリング" TDM研究. 11. 18-22 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Hashimoto: "Clearance mechanisms of atrial and brain natriuretic peptides in rats" Pharm.Res.11. 60-64 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Hashimoto: "Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients" Biol.Pharm.Bull.17. 323-326 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.Takano: "Transport of gentamicin and fluid-phase endocytosis markers in the LLC-PK1 kidney epithelial cell line" J.Pharmacol.Exp.Ther.268. 669-674 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Tanigawara: "Predictive performance of the bayesian analysis:Effects of blood sampling time,population parameters and pharmacostatistical model" J.Pharmacokin.Biopharm.22. 59-71 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.Yasuhara: "Pharmacokinetics and pharmacodynamics of FK506 in pediatric patients receiving living-related donor liver transplantations" Transplant.Proc.27(in press). (1995)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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