Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes.
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.
Otton
S V
SV
Department of Pharmacology and Therapeutics, University of Sheffield, Royal Hallamshire Hospital, England.
Crewe
H K
HK
Lennard
M S
MS
Tucker
G T
GT
Woods
H F
HF
D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003640:Dealkylation; D003647:Debrisoquin / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism*; D007700:Kinetics; D008790:Metoprolol / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology; D013034:Sparteine / Q000378:metabolism*
D007546:Isoquinolines; D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D008790:Metoprolol; D011802:Quinidine; D003647:Debrisoquin