Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique.

The pharmacokinetics of dextro(+)- and levo(-)-verapamii were studied in five healthy volunteers following oral administration of pseudoracemic verapamii containing equal amounts of unlabelled (-)- and dideuterated (+)-isomer. (+)-verapamil exhibited approximately five times greater Cmax (+): 240 ± 81.1 ng/ml, (-): 46.1 ± 15.7 ng/ml, P < 0.001.) and AUC than (-)-verapamil. The apparent oral clearance (CLo) for (+)-verapamil was significantly smaller than that for (-)- verapamil (+): 1.72 ± 0.57 l/min, (-): 7.46 ± 2.16 l/min, P < 0.001). The bioavailability of (+)-verapamil (50%) was 2.5 times greater than that of (-)-verapamil (20%), P < 0.005). Thus following oral administration verapamil exhibited a stereoselective first-pass metabolism. Neither tmax nor the elimination t½,z were different between the isomers. The elimination of t½,z for each verapamil isomer obtained.following oral administration (+): 4.03 h, (-): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (-): 5.38 h, respectively). Whereas the (+)- to (-)-verapamii plasma concentration ratio following oral administration was 4.92 ± 0.48, the ratio following i.v. administration was approximately 2. (-)-verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)-verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (-)-isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction. [ABSTRACT FROM AUTHOR]