Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes

This study demonstrates the stereoselective metabolism of the optical isomers of omeprazole in human liver microsomes. The intrinsic clearance (CL(int)) of the formation of the hydroxy metabolite from S-omeprazole was 10-fold lower than that from R-omeprazole. However, the CL(int) value for the sulfone and 5-O-desmethyl metabolites from S-omeprazole was higher than that from R-omeprazole. The sum of the CL(int) of the formation of all three metabolites was 14.6 and 42.5 microl/min/mg protein for S- and R-omeprazole, respectively. This indicates that S-omeprazole is cleared more slowly than R-omeprazole in vivo. The stereoselective metabolism of the optical isomers is mediated primarily by cytochrome P450 (CYP) 2C19, as indicated by studies using cDNA-expressed enzymes. This is the result of a considerably higher CL(int) of the 5-hydroxy metabolite formation for R- than for S-omeprazole. For S-omeprazole, CYP2C19 is more important for 5-O-desmethyl formation than for 5-hydroxylation. Predictions of the CL(int) using data from cDNA-expressed enzymes suggest that CYP2C19 is responsible for 40 and 87% of the total CL(int) of S- and R-omeprazole, respectively, in human liver microsomes. According to experiments using cDNA-expressed enzymes, the sulfoxidation of both optical isomers is metabolized by a single isoform, CYP3A4. The CL(int) of the sulfone formation by CYP3A4 is 10-fold higher for S-omeprazole than for R-omeprazole, which may contribute to their stereoselective disposition. The results of this study show that both CYP2C19 and CYP3A4 exhibit a stereoselective metabolism of omeprazole. CYP2C19 favors 5-hydroxylation of the pyridine group of R-omeprazole, whereas the same enzyme mainly 5-O-demethylates S-omeprazole in the benzimidazole group. Sulfoxidation mediated by CYP3A4 highly favors the S-form.