EFFECTS OF D,1-VERAPAMIL ON ATRIOVENTRICULAR-CONDUCTION IN RELATION TO ITS STEREOSELECTIVE 1ST-PASS METABOLISM

After the oral administration of 160 mg pseudoracemic verapamil (80 mg d isomer and 80 mg l isomer), the prolongation of the PR interval was assessed in relation to d- and l-verapamil plasma concentrations. Concentration-effect curves were analyzed with the sigmoidal Emax model. Because of stereoselective 1st-pass metabolism, the mean plasma d- to l-verapamil concentration ratio of 4.5 .+-. 1.2 was substantially greater than that of 2.1 .+-. 0.3 after i.v. dosing. Compared with the concentration after i.v. injection, the total verapamil concentration after oral dosing consisted of a substantially smaller proportion of the more potent l-isomer. These differences in isomer composition of the total verapamil plasma concentration as a result of the route of administration explain the diminished negative dromotropic potency of racemic verapamil after oral dosing. The concentration required to reach 50% of the maximum effect (EC50) for total verapamil concentration was 129.0 .+-. 22.9 ng/ml, which was more than 3 times higher than that after i.v. injection. To assess the relative contributions of the d- and l-isomers to overall dromotropic potency, changes in the PR interval were measured after separate oral dosing with 250 mg d-verapamil and 100 mg l-verapamil. The EC50 showed an 11-fold difference between the l- (36.9 .+-. 14.7 ng/ml) and d- (363.1 .+-. 64.2 ng/ml) isomers. The EC50 for the l-isomer concentration after oral pseudoracemic verapamil (20.2 .+-. 6.3 ng/ml) did not differ significantly from that after l-verapamil alone (36.9 .+-. 14.7 ng/ml). The l-isomer determines the negative dromotropic effects of verapamil and that the d-isomer is of minor importance.