Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique (Reprinted from Br J Clin Pharmacol, vol 18, pg 733-740, 1984)

1 The pharmacokinetics of dextro(+)- and levo(-)-verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (-)- and dideuterated (+)-isomer. 2 (+)-verapamil exhibited approximately five times greater C-max (+): 240 +/- 81.1 ng/ ml, (-). 46.1 +/- 15.7 ng/ml, P < 0.001) and AUC than (-)-verapamil. The apparent oral clearance (CL,,) 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 were different stereoselective first-pass metabolism, Neither t(max) nor the elimination t(1/2,z) between the isomers. 3 The elimination of for each verapamil isomer obtained following oral administration (+): 4 03 h, (-) 5.38 h) were similar to those previously obtained following intravenous administration (+): 415 h, (-): 5.38 h, respectively). 4 Whereas the (+)- to (-)-verapamil 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.