USE OF QUINIDINE INHIBITION TO DEFINE THE ROLE OF THE SPARTEINE DEBRISOQUINE CYTOCHROME-P450 IN METOPROLOL OXIDATION BY HUMAN-LIVER MICROSOMES

  • 1 October 1988
    • journal article
    • research article
    • Vol. 247  (1) , 242-247
Abstract
The oxidation of the beta adrenoceptor antagonist metoprolol exhibits genetic polymorphism of the sparteine/debrisoquine (SP/DB) type. The .alpha.-hydroxylation of metoprolol is absent in poor metabolizers, whereas metoprolol O-demethylation is only partially impaired, suggesting that an enzyme or enzymes other than cytochrome P450-SP/DB contribute to the latter reaction. Using inhibition by the quinidine/quinine isomer pair as a marker for the activity of cytochrome P450-SP/DB, the role of this enzyme in the in vitro oxidation of the enantiomers of metoprolol by human liver microsomes was examined. Unlike .alpha.-hydroxylation, only a portion of metoprolol O-demethylation showed the stereoselective inhibition by quinidine and quinine characteristic of in vitro reactions catalyzed by cytochrome P450-SP/DB. Furthermore, the kinetics of metoprolol O-demethylation were biphasic, the two components of O-demethylase activity being distinguishable by their enantioselectivity and sensitivity to inhibition by quinidine. Microsomes from one liver formed no detectable .alpha.-hydroxymetoprolol, and O-demethylation by these microsomes corresponded to the low affinity site observed in eight other livers. The rate of metoprolol O-demethylation by the quinidine-inhibitable high affinity component was directly proportional to the rate of .alpha.-hydroxylation. These findings support the hypothesis that cytochrome P450-SP/DB catalyzes the formation of .alpha.-hydroxymetoprolol, but is only partially responsible for metoprolol O-demethylation. Such a mechanism could explain the previously reported inability to detect polymorphism in the O-demethylation pathway in vivo.

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