Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism.
After the oral administration of 160 mg pseudoracemic verapamil (80 mg dideuterodextro (d) isomer and 80 mg levo (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 first-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 intravenous dosing. Compared with the concentration after intravenous 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 three times higher than that after intravenous 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). We conclude that the l-isomer determines the negative dromotropic effects of verapamil and that the d-isomer is of minor importance.
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008297:Male; D011897:Random Allocation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000097:blood / Q000494:pharmacology*
D014700:Verapamil