Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes.
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)
Kim
M
M
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Shen
D D
DD
Eddy
A C
AC
Nelson
W L
WL
Roskos
L K
LK
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003640:Dealkylation; D003864:Depression, Chemical; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008790:Metoprolol / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology*
D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D008790:Metoprolol