Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes

This study demonstrates the stereoselective metabolism of the optical isome rs of omeprazole in human liver microsomes. The intrinsic clearance (CLint) of the formation of the hydroxy metabolite from S-omeprazole was 10-fold l ower than that from R-omeprazole. However, the CLint value for the sulfone and 5-O-desmethyl metabolites from S-omeprazole was higher than that from R -omeprazole. The sum of the CLint of the formation of all three metabolites was 14.6 and 42.5 mu l/min/mg protein for S- and R-omeprazole, respectivel y. This indicates that S- omeprazole is cleared more slowly than R-omeprazo le in vivo. The stereoselective metabolism of the optical isomers is mediat ed primarily by cytochrome P450 (CYP) 2C19, as indicated by studies using c DNA-expressed enzymes. This is the result of a considerably higher CLint of the 5-hydroxy metabolite formation for R- than for S-omeprazole. For S-ome prazole, CYP2C19 is more important for 5-O-desmethyl formation than for 5-h ydroxylation. Predictions of the CLint using data from cDNA-expressed enzym es suggest that CYP2C19 is responsible for 40 and 87% of the total CLint of S- and R-omeprazole, respectively, in human liver microsomes. According to experiments using cDNA-expressed enzymes, the sulfoxidation of both optica l isomers is metabolized by a single isoform, CYP3A4. The CLint of the sulf one formation by CYP3A4 is 10-fold higher for S-omeprazole than for R-omepr azole, which may contribute to their stereoselective disposition. The resul ts of this study show that both CYP2C19 and CYP3A4 exhibit a stereoselectiv e metabolism of omeprazole. CYP2C19 favors 5-hydroxylation of the pyridine group of R-omeprazole, whereas the same enzyme mainly 5-O-demethylates S-om eprazole in the benzimidazole group. Sulfoxidation mediated by CYP3A4 highl y favors the S-form.