RT Journal Article
SR Electronic
T1 Quantitative Prediction of Metabolic Inhibition of Midazolam by Itraconazole and Ketoconazole in Rats: Implication of Concentrative Uptake of Inhibitors into Liver
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 395
OP 402
VO 27
IS 3
A1 Yamano, Katsuhiro
A1 Yamamoto, Koujirou
A1 Kotaki, Hajime
A1 Sawada, Yasufumi
A1 Iga, Tatsuji
YR 1999
UL http://dmd.aspetjournals.org/content/27/3/395.abstract
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