Abstract

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 fromS-omeprazole was higher than that fromR-omeprazole. The sum of the CL_int of the formation of all three metabolites was 14.6 and 42.5 μl/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 forR- than for S-omeprazole. ForS-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- andR-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 forR-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 ofR-omeprazole, whereas the same enzyme mainly 5-O-demethylates S-omeprazole in the benzimidazole group. Sulfoxidation mediated by CYP3A4 highly favors theS-form.