Stereoselective metabolism by human liver CYP enzymes of a substituted benzimidazole

H 259/31 is a substituted benzimidazole developed as a structural analog of omeprazole. Metabolites of H 259/31 formed in human liver microsomes were identified by using the synthetic reference compounds and liquid chromatogr aphy/mass spectrometry. The predominant metabolic pathways found include ox idation of the sulfoxide to sulfone, oxidative O-dealkylation of the cyclop ropylmethoxy group to the corresponding pyridone and aromatic hydroxylation to give the phenolic derivative. Stereoselectivity in the metabolism of th e enantiomers of H 259/31 was demonstrated in human liver microsomes. The s um of the formation intrinsic clearances of all three metabolites was highe r for the S-enantiomer than that of the R-form, indicating that the S-enant iomer is eliminated more rapidly. It was also shown in the present study th at the sulfone metabolite is subject to additional metabolism, which should be taken into account when determining the intrinsic clearance for formati on of metabolites and when the relative importance of metabolic pathways is determined. Expressed enzymes indicate major involvement of cytochrome P-4 50 (CYP) 2C19 in the formation of the hydroxy derivative as well as in pyri done formation from the enantiomers of H 259/31. CYP3A4 and CYP2C9 seem to contribute as low-affinity enzymes in both reactions. The sulfone metabolit e was formed mainly from CYP3A4. Stereoselectivity in CYP3A4-, CYP2C19-, an d CYP2C9-mediated metabolic pathways was demonstrated.