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Quantitative evaluation of drug interactions and development of a prescription-supporting system for the avoidance of adverse effects

Research Project

Project/Area Number 10357022
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionThe University of Tokyo

Principal Investigator

IGA Tatsuji  Dept. of Pharmacy, Univ. of Tokyo Hospital, Professor, 医学部・附属病院, 教授 (60012663)

Co-Investigator(Kenkyū-buntansha) ORII Takao  Dept. of Pharmacy, Univ. of Tokyo Hospital, Assis. Professor, 医学部・附属病院, 助手 (50231246)
SATO Hitoshi  Dept. of Pharmacy, Univ. of Tokyo Hospital, Assoc. Professor, 医学部・附属病院, 助教授 (40187224)
SAWADA Yasufumi  Faculty of Pharmaceutical Sciences, Kyushu Univ., Professor, 大学院・薬学研究科, 教授 (80114502)
NAKANO Shigeyuki  Faculty of Medicine, Ohita Medial Univ., Professor, 医学部, 教授 (10033341)
HIGUCHI Shun  Faculty of Pharmaceutical Sciences, Kyushu Univ., Professor, 大学院・薬学研究科, 教授 (40218699)
大江 和彦  東京大学, 医学部・附属病院, 教授 (40221121)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥32,700,000 (Direct Cost: ¥32,700,000)
Fiscal Year 1999: ¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 1998: ¥20,300,000 (Direct Cost: ¥20,300,000)
Keywordsdrug interaction / avoidance of side effects / Prescription-inspection supporting system / drug information / clinical trials / pharmacogenetics / 処方オーダリング / クリアランス理論 / P-糖タンパク質 / グレープフルーツジュース / データベース
Research Abstract

1) Mechanism of drug interactions : Drug-grape fruit juice (GFJ) interaction studies were undertaken to clarify the mechanism of drug interactions at the gut tissue. We have found that a GFJ component, dihydroxy vergamotine, inhibited the efflux activity of P-glyco-protein. It was thus suggested that, according to this inhibitory mechanism on Pglycoproptein as well as on P450 enzymes, GFJ enhances the drug absorption of drugs, by which plasma concentrations of drugs may inrease.
2) Establishment of a prediction method of drug interactions in preclinical phases and dose setting for clinical trials : Modelling analysis was carried out to predict drug interactions quantitatively, using a Ca-blocker, felodipine, and an immunosuppresant, cyclosporine, as model compounds. We attempted to predict the contributions of the liver and gut in drug interactions based on clearance theory from in vivo and in vitro experiments using rats. As a result, it has been successful to predict the increase in d … More rug concentrations in blood by calculating drug concentrations in the liver and gut using a new method of predicting inhibitor concentrations in these tissues. Moreover, it has become possible in this study to estimate the increase in drug concentrations in blood in humans when an inhibitor is coadministered.
3) Investigation of genetic polymorphism : With regard to CYP2C19, we found that the clearance value of people showing wt/m1 and wt/m2, which have been conventionally classified as extensive metabolizer (EM), falls between the clearance values in EM and poor metabolizer (PM), indicating that heterozygous polymoriphisms lead to the reduction of metabolic activities. In patients with gastric ulcer, clinical effect (examination of ulcer improvement using an endoscope) of omeprazole, given at regular doses indicated in drug labelling, was 83% for PM and 32% for EM, which should be the manifestation of reduced clearance in PM. The short period of time required for ulcer healing was also shorter in PM.
4) Construction of information on dose settings and choice of medicine to avoid interactions of drugs in the market : We conducted a retrospective survey of clinical cases for drug interactions, and established a dose setting method, be used alternatively for particular drugs which may interact with co-administered drugs.
5) Development of software to search drug information on drug interaction avoidance : We created a database of drug information on drug interactions, by which we can rapidly search the combination of drug interactions. Software for personal computers was then implemented to analyze possible drug interactions based on the above database, which can be easily utilized in clinical settings.
6) Establishment and evaluation of an order entry system to provide drug information on drug interactions : By incorporating the above mentioned software into the conventional order entry system, we developed an order entry/prescription auditing system for drug interactions in the University of Tokyo Hospital. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] 伊賀立二: "Development and evaluation of a prescription-inspecting supporting system for rational use of medications(I)"Yakugaku Zasshi. 118. 168-178 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Development and assessment of an inspection-supporting system using drug images for unit dose packages"Yakugaku Zasshi. (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Running-state of the outpatient ocnsultation records based on an in-hospital LAN."Jpn. J. Hosp. Pharm.. (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats : implication of concentrative uptake of inhibitors into liver."J. Pharmacol. Exp. Ther.. 292. 1118-1126 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Effect of itraconazole on the pharmacokinetics of digoxin in guinea pig."Biopharm. Drug. Dispos.. 20. 145-149 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats."J. Pharm. Sci.. 88. 234-240 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats : implication of concentrative uptake of inhibitors into liver."Drug Metab. Dispos.. 27. 395-402 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Simvastatin-tacrolimus and simvastatin-cyclosporin interactions in rats."Biopharm. Drug Dispos.. 19. 272-402 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Effect of cilastatin on renal handling of vancomycin in rats."J. Pharm. Sci.. 87. 1173-1176 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Quantitative prediction of the interaction of midazolam and histamine H2 receptor antagonists in rats."Drug Metab. Dispos.. 26. 318-323 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立二: "Neurotoxicodynamics of the interaction between ciprofloxacin and foscarnet in mice."Antimicrob. Agents Chemother.. 42. 691-694 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 澤田康文: "Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model."Br J Clin Pharmacol.. 49. 49-58 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 澤田康文: "Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier."Biopharm. Drug Dispos.. 20. 85-90 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 澤田康文: "P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier."Antimicrob. Agents Chemother.. 42. 1738-1744 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 澤田康文: "Inhibition of vinblastine efflux mediated by P-glycoprotein by grapegruit juice components in Caco-2 cells."Biol. Pharm. Bull.. 21. 1062-1066 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 樋口駿: "Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping : possible effect of age, liver disease and length of therapy."Br J Clin Pharmacol.. 47. 115-119 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 樋口駿: "The Effects of Genetic Polymorphisms of CYC2C9 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy : Studies in Stereoselective Hydroxylation and Population Pharmacokinetics."Epilesia. 39. 1317-1332 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 樋口駿: "Genetic Polymorphism of Cytochrome P450s, CYP2C9 in Japanese Population."Therapeutic Drug Monitoring. 20. 243-247 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Development and evaluation of a prescription-inspecting supporting system for rational use of medications (I)."Yakugaku Zasshi. 118. 168-178 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Development and assessment of an inspection-supporting system using drug images for unit dose packages."Yakugaku Zasshi. in press. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Running-state of the outpatient ocnsultationon for drug compliance and development of a management system of the consultation records based on an in-hospital LAN."Jpn. J. Hosp. Pharm.. in press. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats : implication of concentrative uptake of inhibitors into liver."J. Pharmacol. Exp. Ther.. 292. 1118-1126 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Effect of itraconazole on the pharmacokinetics of dioxin in guinea pigs."Biopharm. Drug Dispos. 20. 145-149 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats."J. Pharm. Sci.. 88. 234-240 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats : implication of concentrative uptake of inhibitiors into liver."Drug Metab. Dispos.. 27. 395-402 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Simvastatin-tacrolimus and simvastatin-cyclosporin interactions in rats."Biopharm. Drug Dispos.. 19. 279-284 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Effect of cilastatin on renal handling of vancomycin in rats."J. Pharm. Sci.. 87. 1173-1176 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Quantitative prediction of the interaction of midazolam and histamine H2 receptor antagonists in rats."Drug Metab. Dispos.. 26. 318-323 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iga, T.: "Neurotoxicodynamics of the interaction between ciprofloxacin and foscarnet in mice."Antimicrob. Agents Chemother.. 42. 691-694 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sawada, Y.: "Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model."Br J Clin Pharmacol.. 49. 49-58 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sawada, Y.: "Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier."Biopharm. Drug Disp.. 20. 85-90 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sawada, Y.: "P-glycoprotein -mediated transport of itraconazole across the blood-brain barrier."Antimicrob. Agents Chemother.. 42. 1738-1744 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sawada, Y.: "Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells."Biol. Pharm. Bull.. 21. 1062-1066 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Higuchi, S.: "Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping : possible effect of age, liver disease and length of therapy."Br J Clin Pharmacol. 47. 115-119 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Higuchi, S.: "The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy : Studies in Stereoselective Hydroxylation and Population Pharmacokinetics."Epilepsia. 39. 1317-1323 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Higuchi, S.: "Genetic Polymoriphism of Cytochrome P450s, CYP2C19, and CYP2C9 in Japanese Population."Therapeutic Drug Monitoring. 20. 243-247 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 伊賀立ニ,澤田康文,その他: "Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats : implication of concentrative uptake of inhibitors into liver"J. Pharmacol Exp. Ther.. 292. 1118-1126 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊賀立ニ,澤田康文,その他: "Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats : implication of concentrative uptake of inhibitors into liver"Drug Metab. Dispos.. 27. 395-402 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊賀立ニ,澤田康文,その他: "Correlation between in vivo and in vitro hepatic uptake of metabolic inhibitors of cytochrome P-450 in rats"Drug Metab. Dispos.. 27. 1225-1231 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 樋口 駿,その他: "Reliability of the omeprazole hydroxylation index for CYP2C9 phenotyping : possible effect of age liver disease and length of therapy"Br. J. Clin. Pharmacol.. 47. 115-119 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 樋口 駿,その他: "CYP2C9 polymorphism effect on phenobarbitione pharmacokinetics in Japanese patients with epilepsy : Analysis by population pharmacokinetics"Eur. J. Clin. Pharmacol.. (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊賀立ニ,沢田康文,その他: "Inhibition of vinblastin efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells"Biol. Pharm. Bull.. 21. 1062-1066 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊賀立ニ,その他: "癌化学療法時の薬物相互作用"先端医学社. 462 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊賀立ニ: "医薬品情報学(第2版)"東京大学出版会. 248 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊賀立二、澤田康文 他: "Neurotoxicodynamics of the interaction between ciprofloxacin and foscarret in mice" Antimicrob.Agents Chemother.42. 691-694 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 伊賀立二、澤田康文 他: "P-glycoprotein-mediated transport of itracorazole across the blood-brain barrier" Antimicrob.Agents Chemother.42. 1738-1744 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 伊賀立二、澤田康文 他: "Quantitative prodiction of midazolam and histamine Hi-receptor antagonists interaction in rats" Drug Metab.Dispos.26. 318-323 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 伊賀立二、澤田康文 他: "Simuastatin-facrolimus and simuastatin-cyclosporin interaction in rats" Biopharm.Drug Dispos.19. 279-284 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 澤田康文 他: "Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice compoross in Caco-2 cells" Biol.Pharm.Bull.21. 1062-1066 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 樋口 駿 他: "Association of polymorphisus in the cytochrome P450(CYP)2C19 and 2C18 genes in Japanese epileptic patient" Pharmacogenetics. 8. 87-90 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 伊賀立二: "医薬品情報学(第2版)" 東京大学出版会, 248 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山田安彦、高柳理早、伊賀立二: "癌化学療法時の薬物間相互作用" 先端医学社, 462 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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