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Pharmacokinetic Studies on Drug Excretion Mechanism Mediated by P-Glycoprotein

Research Project

Project/Area Number 06672233
Research Category

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

Allocation TypeSingle-year Grants
Research Field 医薬分子機能学
Research InstitutionKOBE UNIVERSITY

Principal Investigator

TANIGAWARA Yusuke  Kobe University University Hospital Faculty of Medicine Associate Professor, 医学部・附属病院, 助教授 (30179832)

Co-Investigator(Kenkyū-buntansha) OKUMURA Katsuhiko  Kobe University University Hospital Faculty of Medicine Professor, 医学部・附属病院, 教授 (60025707)
UEDA Kazumitsu  Kyoto University Faculty of Agriculture Instructor, 農学部, 助手 (10151789)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsP-glycoprotein / MDR / Cyclosporin / PSC 833 / Reversal of resistance / Pharmacokinetics / Doxorubicin / Multidrug resistance / 薬物排泄 / 抗がん剤 / 薬剤耐性 / トランスポーター
Research Abstract

To investigate a mechanism of drug transport by P-glycoprotein, a quantitative analysis has been performed for structure-activity relationships. The drug transport by P-glycoprotein was measured by a transcellular transport system by introducing human MDRI cDNA into a porcine kidney epithelial cell line, LLC-PK_1.
The first study using a series of steroids showed that cortisol and dexamethasone, which are relatively lower lipophilic steroids, were well transported by P-glycoprotein, but that they did not possess an inhibitory effect on P-glycoprotein-mediated transport of drugs. On the other hand, steroids with higher lipophilicity showed a strong inhibitory effect, while they were not transported by P-glycoprotein. The transporting activity was not consistent with the inhibitory activity, suggesting a multiplicity of transporting mechanism of P-glycoprotein.
The next study investigated the inhibitory effect of cyclosporin analogs on P-glycoprotein-mediated transcellular transport of sev … More eral anticancer agents. The lipophilic cyclosporin analogs inhibited P-glycoprotein-mediated transport of daunorubicin, doxorubicin and vinblastine. The rank order of the inhibitory activity was SDZ PSC 833 > cyclosporin D,dihydrocyclosporin D > cyclosporin A > cyclosporin C,dihydrocyclosporin C.The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect depended on the concentration of cyclosporins. The inhibitory effect on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity.
The phase I study of the combination of the most potent agent, SDZ PSC 833 and doxorubicin was conducted to determine the maximum tolerated dose of these two agents as well as to investigate the drug interaction in pharmacokinetics. The doxorubicin clearance was decreased with increased blood concentration of SDZ PSC 833, indicating that the inhibition of P-glycoprotein function could change drug distribution and elimination. These findings are useful for developing a new chemotherapy to target P-glycoprotein. Less

Report

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

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Y.TANIGAWARA: "Predictive performance of the Bayesian analysis : Effect of blood sampling time, population parameters and pharmacostatical modil" Jpurnal of Pharmacokinetics and Biopharmaceutics. 22. 59-71 (1994)

    • 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" Biological Pharmaceutical Bulletin. 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] Y.TANIGAWARA: "Premarketing poplation pharmacokinetic study of levofloxacin in normal subjects and patients iwth infections diseases" Biological Pharmaceutical Bulletin. 18. 315-320 (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 multidmg resistant modifier, is a substrate for P-glycoprotein" Journal of Pharmacology and Expevimental therapaitics. 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.TANIGAWARA: "Population pharmacokinetics of theophylline. III : Premarketing Study for a once-daily administered preparation" Biological Pharmaceutical Bulletin. 18. 1590-1598 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.NISHIGUCHI: "Effects of tramsfection with Cu,Zn-spenoxide dismutase gene on xanthine/xanthineoxidase-induced cytotoxicity in fibroblasts from rat skin" Pharmaceutical Research. 13. 575-580 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] D.Keppler: "Transport in the Liver" Kluwer Academic Publishers, 258 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 伊賀立二: "薬物間相互作用と医薬品の適正使用" 薬業時報社, 486 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Tanigawara: "Predictive Performance of the Baysian Analysis : Effects of Blood Sampling Time, Population Parameters and Pharmacostatistical Model" J.Pharmacokin.Biopharm.22. 59-71 (1994)

    • Description
      「研究成果報告書概要(欧文)」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] Y.Tanigawara: "Premarketing Population Pharmacokinetic Study of Levofloxacin in Normal Subjects and Patients with Infectious Diseases" Biol.Pharm.Bull.18. 315-320 (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.Tanigawara: "Population Pharmacokinetics of Theophylline. III : Premarketing Study for a Once-Daily Administered Preparation" Biol.Pharm.Bull.18. 1590-1598 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Nishiguchi: "Effects of Transfection with Cu, Zn-Superoxide Dismutase Gene on Xanthine/Xanthine Oxidase-Induced Cytotoxicity in Fibroblasts from Rat Skin" Pharm.Res.13. 575-580 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] D.Keppler: "Transport in the Liver". Kluwer Academic Publishers, 258 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Iga: "Drug Interactions and Proper Use of Drugs". Yakugyo Jiho Sha, 486 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. TANIGAWARA: "Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infections diseases." Biological Pharmacentical Bulletin. 18. 315-320 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] M. HIRAI: "Cepharanthin, a multidrug resistant modifier, is a substrate for P-glycoprotein" Journal of Pharmacology and Experimental Therapeutics. 275. 73-78 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y. TANIGAWARA: "Population pharmacokinetics of theophylline.III: Premarketing study for a once-daily administered preparation." Biological Pharmacentical Bulletin. 18. 1590-1598 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] K. NISHIGUCHI: "Effect of transfection with Cu, Zn-superoxide dismutase gene on xanthine/Xanthine oxidase-induced cytotoxicity in fibroblasts from rat skin" Pharmaceutical Research. 13. 575-580 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] F. KOMADA: "Effect of transfection with a superoxide dismutase expression plasmid on superoxide anion induced cytotoxicity in cultured rat lung cells" Biological Pharmaceutical Bulletin. 19. 274-279 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] 伊賀 立二: "薬物間相互作用と医薬品の適正使用" 薬業時報社, 486 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y.TANIGAWARA: "Predictive performance of the Bayesian Analysis : Effect of blood sampling time,population parameters and pharmacostatistical model" Journal of Pharmacokinetics and Biopharmaceutics. 22. 59-71 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.HASHIMOTO: "Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients" Biological Pharmaceutical Bulletin. 17. 323-326 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 堀 了平: "日本人における薬物動態母集団パラメータの推定(1):ジゴキシン" TDM研究. 11. 7-17 (1994)

    • Related Report
      1994 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] 寺川 雅人: "バミカミドのpopulation phamacodynamics" 臨床薬理. 25. 603-613 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] D.Keppler: "Transport in the Liver" Kluwer Academic Publishers, 258 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 伊賀 立二: "能動的医薬品情報提供活動と処方設計支援" 薬業時報社, 488 (1994)

    • Related Report
      1994 Annual Research Report

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

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