Use of Quinidine Inhibition to Define the Role of the

The oxidation of the beta adrenoceptor antagonist metoprolol exhibits genetic polymorphism of the sparteine/debrisoquine (SP/DB) type. The a-hydroxylation of metoprolol is absent in poor metabolizers, whereas metoprolol 0-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 a-hydroxyl-ation, 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 0-demethylation wer