Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats: Implication of concentrative uptake of inhibitors into liver

To evaluate the degree of drug-drug interaction concerning metabolic inhibi tion in the liver quantitatively, we tried to predict the plasma concentrat ion increasing ratio (R) of midazolam (MDZ) by erythromycin (EM), diltiazem (DLZ), or verapamil (VER) in rats. MDZ was administered through the portal vein at the steady state of plasma concentration of these inhibitors. The R values in the area under the plasma concentration curve of MDZ in the pre sence of EM, DLZ, and VER were 2.02, 1.64, and 1.30, respectively. The live r to plasma unbound concentration ratios of EM, DLZ, and VER at the steady state after infusion were 20.8, 1.02, and 3.01, respectively, suggesting co ncentrative uptake of EM and VER into the liver. The predicted R value in t he presence of EM calculated by use of plasma unbound concentration was 1.0 3, whereas the value calculated with liver unbound concentration was 1.61, which was very close to the observed value. These findings indicated the ne ed to consider the concentrative uptake of inhibitors into the liver for th e quantitative prediction of metabolic inhibition. However, the predicted v alues in the presence of DLZ or VER calculated by use of liver unbound conc entration were still underestimated. This result may be due to the metaboli c inhibition by the metabolites of both inhibitors. Therefore, when predict ing the degree of metabolic inhibition quantitatively, the inhibitory effec t by coadministered drugs and the disposition of these metabolites in the l iver must also be considered.