Stereoselective metabolism of cibenzoline, an antiarrhythmic drug, by human and rat liver microsomes: Possible involvement of CYP2D and CYP3A

Stereoselective metabolism of cibenzoline succinate, an oral antiarrhythmic drug, was investigated on hepatic microsomes from humans and rats and micr osomes from cells expressing human cytochrome P450s (CYPs). Four main metab olites, M1 (p-hydroxycibenzoline), M2 (4,5-dehydrocibenzoline), and unknown metabolites M3 and M4, were formed by human and rat liver microsomes. The intrinsic clearance (CLint) of the M1 formation from R(+)-cibenzoline was 2 3-fold greater than that of S(-)-cibenzoline in human liver microsomes, whe reas the R(+)/S(-)-enantiomer ratio of CLint for M2, M3, and M4 formation w as 0.39 to 0.83. The total CLint for the formation of the four main metabol ites from S(-)- and R(+)-cibenzoline was 1.47 and 1.64 mu l/min/mg, respect ively, suggesting that the total CLint in R(+)-enantiomer was slightly grea ter than that in S(-)-enantiomer in human liver microsomes. The M1 formatio n from R(+)-cibenzoline was highly correlated with bufuralol 1'-hydroxylati on and CYP2D6 content and was inhibited by quinidine, a potent inhibitor of CYP2D6. Additionally, only microsomes containing recombinant CYP2D6 were c apable of M1 formation. These results suggest that the M1 formation from R( +)-cibenzoline was catalyzed by CYP2D6. The formation of M2, M3, and M4 fro m S(-)- and R(+)-cibenzoline was highly correlated with testosterone 6 beta -hydroxylation and CYP3A4 content. Ketoconazole, which is a potent inhibito r of CYP3A4/5, had a strong inhibitory effect on their formation, and the M 4 formation from R(+)-cibenzoline was inhibited by quinidine by 45%. The fo rmation of M2 was also inhibited by quinidine by 46 to 52% at lower cibenzo line enantiomers (5 mu M), whereas the inhibition by quinidine was not obse rved at a higher substrate concentration (100 mu M). In male rat liver micr osomes, ketoconazole and quinidine inhibited the formation of the main meta bolites, M1 and M3, >74% and 44 to 59%, respectively. These results provide evidence that CYP3A and CYP2D play a major role in the stereoselective met abolism of cibenzoline in humans and male rats.