RT Journal Article SR Electronic T1 Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 309 OP 317 VO 21 IS 2 A1 M Kim A1 D D Shen A1 A C Eddy A1 W L Nelson A1 L K Roskos YR 1993 UL http://dmd.aspetjournals.org/content/21/2/309.abstract AB In an effort to investigate the metabolic basis of previously reported pharmacokinetic interactions between beta-adrenergic antagonists and calcium channel blockers, the effects of verapamil on the oxidative metabolism of metoprolol were studied in microsomes isolated from four human livers. Deuterium-labeled pseudoracemic metoprolol was used to characterize the substrate stereoselectivity of this metabolic interaction. Biphasic kinetics were observed for both the alpha-hydroxylation and O-demethylation of metoprolol, suggesting that multiple P-450 enzymes with differing KMs are involved in the formation of these oxidative metabolites. alpha-Hydroxylation showed a slight preference for S-(-)-metoprolol, and it was largely mediated by a high-affinity enzyme over a wide range of substrate concentrations. The high-affinity component of the O-demethylation reaction exhibited significant selectivity for the R-(+)-enantiomer. The opposite enantioselectivity was observed for the low-affinity component of O-demethylation. Racemic verapamil inhibited both the alpha-hydroxylation and the O-demethylation of metoprolol. The kinetics of inhibition were consistent with competitive effects of verapamil on the high-affinity components of both oxidative pathways, which previously had been suggested to be mediated by CYP2D6. Potent inhibition of the low-affinity component of O-demethylation was also observed. The inhibitory effect of verapamil on the alpha-hydroxylation of metoprolol was not enantioselective. On the other hand, verapamil preferentially inhibited the O-demethylation of R-(+)-metoprolol compared with S-(-)-metoprolol at low substrate concentration.(ABSTRACT TRUNCATED AT 250 WORDS)