In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone

Publisher Website
Google Scholar
Abstract
Propafenone is a new class 1 antiarrhythmic agent. The drug is extensively metabolized. 5-Hydroxylation and N-dealkylation constitute major metabolic pathways. Recently it has been demonstrated that the in vivo metabolism of propafenone is controlled by the debrisoquin/sparteine polymorphism. To elucidate which of the above metabolic reactions is catalyed by cytochrome P-450dbl, the formation of 5-hydroxypropafenone and N-desalkylpropafenone was studied in the microsomal fraction of four human kidney donor livers previously characterized with regard to their ability to hydroxylate the .beta.-adrenergic antagonist bufuralol. The l''hydroxylation of bufuralol is catalyzed by the P-450dbl responsible for polymorphic debrisoquin/sparteine oxidation. The formation of 5-hydroxypropafenone but not N-desalkylpropafenone was closely related to bufuranlol l''hydroxylation. Incubation with LKM1 antibodies, which selectively recognize P-450db1, inhibited 5-hydroxypropafenone formation completely whereas N-dealkylation was unimpaired. Propafenone was a strong competitive inhibitor of bufuralol l''hydroxylation. Thus it can be concluded that 5-hydroxypropafenone is formed by the cytochrome P-450 isozyme involved in polymorphic bufuralol oxidation.