Abstract

Incubation of R(+)- and S(-)-carvedilol with rat liver microsomes showed the formation of four oxidative metabolites: 1-hydroxycarvedilol (1-OHC), 8-hydroxycarvedilol (8-OHC), 4'-hydroxycarvedilol (4'-OHC), and O-desmethylcarvedilol (DesC). The structures of these metabolites were confirmed by cochromatography with the authentic metabolites and by thermospray ms. As expected from in vivo metabolism studies, 1-OHC and 8-OHC were the major products for both enantioners used as a substrate. The S/R enantiomeric ratios for intrinsic clearance (Vmax/KM) of 1-OHC, 8-OHC, DesC, and 4'-OHC were 0.40, 1.99, 0.77, and 2.71, respectively, showing that stereoselective oxidation occurs in this species. These findings strongly suggest that the stereoselective biliary excretion of the two major carbazole ring-hydroxylated glucuronides, 1-hydroxycarvedilol O-glucuronide, and 8-hydroxycarvedilol O-glucuronide observed previously in rats can be explained by stereoselective hydroxylation in liver. The cause of the difference in intrinsic clearance for 1-OHC and 8-OHC between the two enantiomers was based on the difference in affinity to the catalyzing enzyme. The main enzyme concerned in the 1- and 8-hydroxylation of both enantiomers is considered to be CYP2D1 from the following observation: the marked strain differences between Sprague-Dawley and Dark Agouti rats and competitive inhibition by quinine. In the O-demethylation of both enantiomers, CYP2C11 is probably the major catalyzing enzyme, because sex differences, but no strain difference, were observed in both Sprague-Dawley and Dark Agouti rats, and also anti-CYP2C11 strongly inhibited this demethylation.