Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes.

ABSTRACT

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)