Quantitative prediction of the interaction on hepatic metabolism of midazolam

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  • YAMANO Katsuhiro
    Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine University of Tokyo
  • YAMAMOTO Koujirou
    Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine University of Tokyo
  • KOTAKI Hajime
    Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine University of Tokyo
  • TAKETOMI Sayuri
    Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University
  • MATSUO Hirotami
    Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University
  • SAWADA Yasufumi
    Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University
  • IGA Tatsuji
    Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine University of Tokyo

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  • ミダゾラムの肝薬物代謝に関する相互作用の定量的予測

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(1) We tried to predict the increase rate (F) of plasma concentration or miaazolam (MDZ) in the presence of inhibitors in rats, using the following equation. F=1+Ci/Ki (Ci:concentration of inhibitor, Ki:inhibitory constant). The predicted F in the presence of itraconazole, ketoconazole, cimetidine, and nizatidine using unbound concentrations of inhibitors in the liver were close to the observed values, suggesting the concentrative uptake of inhibitors into the liver must be taken into consideration to predict F. (2) There was a good correlation between the cell-to-medium concentration ratio (C/M) and the liver-to-unbound plasma concentration ratio (Kpf) in rats, suggesting drug concentration in the liver can be predicted from C/M and unbound plasma concentration. (3) We attemptted to predict F of plasma concentration of MDZ in the presence of inhibitors in human from absorption constant and Kpf in rats. The predicted F in the presence of cimetidine corresponded to the observed value.

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