CYTOCHROME-P450 SPECIFICITY OF METABOLISM AND INTERACTIONS OF OXYBUTYNIN IN HUMAN LIVER-MICROSOMES

Oxybutynin has an extensive first pass metabolism after oral administr ation, the main active metabolite being N-desethyloxybutynin. The purp ose of this study was to investigate the CYP isoform specificity of os ybutynin N-de-ethylation and possible interactions. Oxybutynin N-deeth ylation in human liver microsomes ill vitro was potently inhibited by ketoconazole (IC50 4.5 mu M): less and variably by itraconazole and no t by quinidine or several other reference inhibitors, suggesting that CYP3A enzymes are predominant catalysts of the reaction. Recombinant C YP3A5 enzyme had higher activity in osybutynin N-deethylation than rec ombinant CYP3A4. Ketoconazole inhibited osybutynin N-deethylation by t he recombinant CYP3A4 and CYP3A5 almost completely, whereas itraconazo le inhibited the activity of CYP3A4 more potently than that of CYP3A5. Oxybutynin inhibited CYP3A4- and CYP2D6- associated activities (testo sterone 6 beta-hydroxylase and dextromethorphan O-demethylase, respect ively) in human liver microsomes. CYP1A1/2-, CYP2A6-, CYP2C9- and CYP2 E1- associated activities were inhibited less potently or not at all b y oxybutynin when compared with reference inhibitors. Although the rea sons for the weak and variable inhibition by itraconazole remain to be studied, it seems that osybutynin is predominantly metabolized by CYP 3A4 and CYP3A5 but not by CYP2D6. However, it seems to have some affin ity also to the latter enzyme.