PT  - JOURNAL ARTICLE
AU  - Yamano, Katsuhiro
AU  - Yamamoto, Koujirou
AU  - Kotaki, Hajime
AU  - Sawada, Yasufumi
AU  - Iga, Tatsuji
TI  - Quantitative Prediction of Metabolic Inhibition of Midazolam by Itraconazole and Ketoconazole in Rats: Implication of Concentrative Uptake of Inhibitors into Liver
DP  - 1999 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 395--402
VI  - 27
IP  - 3
4099  - http://dmd.aspetjournals.org/content/27/3/395.short
4100  - http://dmd.aspetjournals.org/content/27/3/395.full
SO  - Drug Metab Dispos1999 Mar 01; 27
AB  - 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, usingKi 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. The American Society for Pharmacology and Experimental Therapeutics