The influence of cimetidine on the pharmacokinetics of diltiazem and its main metabolite in rabbits

The purpose of this study was to investigate the pharmacokinetic alteration of diltiazem and its main metabolite, deacetyldiltiazem, after oral administration of diltiazem in rabbits with or without cimetidine co-administration. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly elevated in rabbits pretreated with cimetidine, suggesting that the oral clearance, an index of intrinsic clearance, may be decreased by the cimetidine treatment. Consistent with the increased AUC by the treatment, peak plasma concentration (Cmax) for diltiazem was also elevated. Apparent volume of distribution normalized by the bioavailability (Vd/F) of diltiazem increased significantly in rabbits pretreated with cimetidine increased. Taken together with the fact that the first pass metabolism for diltiazem is the primary determinant for the oral bioavailability, these observations indicate that increases in the oral clearance and Vd/F may be a manifestation of the decreased first pass metabolism. Consistent with the hypothesis, the AUC of deacetyldiltiazem was significantly decreased in rabbits with cimetidine treatment. Ratio of deacetyldiltiazem to total diltiazem in the plasma was significantly decreased in rabbits with cimetidine treatment. These observations suggested that the metabolism of diltiazem to deacetyldiltiazem was reduced by cimetidine treatment and that the dosage of diltiazem should be adjusted when the drug is co-administered chronically with cimetidine in a clinical setting.