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Vol. 27, Issue 3, 395-402, March 1999
Biopharmaceutical and Pharmacokinetic Research Laboratories,
Fujisawa Pharmaceutical Co., Ltd., Kashima, Yodogawa-ku, Osaka, Japan
(Ka.Y.);
Department of Clinical Pharmacology School of Medicine, Gunma
University, Showa machi, Maebashi, Japan (Ko.Y.);
Department of
Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University
of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan (Ka.Y., H.K., T.I.); and
Faculty of Pharmaceutical Sciences, Kyushu University, Maidashi,
Higashi-ku, Fukuoka, Japan (Y.S.)
To evaluate the extent of drug-drug interaction concerning
metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio of midazolam (MDZ) by itraconazole (ITZ) or ketoconazole (KTZ) in rats. MDZ was administered at a dose of 10 mg/kg through the portal vein at 60 min after bolus
administration of 20 mg/kg ITZ or during 0.33 mg/h/body of KTZ
infusion. The ratio values in the area under the plasma concentration
curve of MDZ in the presence of ITZ and KTZ was 2.14 and 1.67, respectively. The liver-unbound concentration to plasma-unbound
concentration ratios of ITZ and KTZ were 11~14 and 1.3, respectively, suggesting a concentrative uptake of both drugs into the
liver. ITZ and KTZ competitively inhibited the oxidative metabolism of
MDZ in rat liver microsomes, and Ki values of
ITZ and KTZ were 0.23 µM and 0.16 µM, respectively. We predicted the ratio values of MDZ in the presence of ITZ and KTZ, using Ki values and unbound concentrations of both
drugs in the plasma or liver. The predicted ratio values in the
presence of ITZ or KTZ calculated by using unbound concentration in the
plasma were 1.03~1.05 and 1.39, whereas those calculated using
unbound concentration in the liver were 1.73~1.97 and 1.51, respectively, which were very close to the observed ratio values. These
findings indicated the necessity to consider the concentrative uptake
of inhibitors into the liver for the quantitative prediction of the
drug-drug interactions concerning metabolic inhibition in the liver.
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