Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats: Implication of concentrative uptake of inhibitors into liver

To evaluate the extent of drug-drug interaction concerning metabolic inhibi tion in the liver quantitatively, we tried to predict the plasma concentrat ion increasing ratio of midazolam (MDZ) by itraconazole (ITZ) or ketoconazo le (KTZ) in rats. MDZ was administered at a dose of 10 mg/kg through the po rtal 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 1.6 7, respectively. The liver-unbound concentration to plasma-unbound concentr ation ratios of ITZ and KTZ were 11 similar to 14 and 1.3, respectively, su ggesting a concentrative uptake of both drugs into the liver. ITZ and KTZ c ompetitively inhibited the oxidative metabolism of MDZ in rat liver microso mes, and K-i values of ITZ and KTZ were 0.23 mu M and 0.16 mu M, respective ly. We predicted the ratio values of MDZ in the presence of ITZ and KTZ, us ing K-i values and unbound concentrations of both drugs in the plasma or li ver. The predicted ratio values in the presence of ITZ or KTZ calculated by using unbound concentration in the plasma were 1.03 similar to 1.05 and 1. 39, whereas those calculated using unbound concentration in the liver were 1.73 similar to 1.97 and 1.51, respectively, which were very close to the o bserved ratio values. These findings indicated the necessity to consider th e concentrative uptake of inhibitors into the liver for the quantitative pr ediction of the drug-drug interactions concerning metabolic inhibition in t he liver.