Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes.

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Abelo A, Andersson TB, Antonsson M, Naudot AK, Skanberg I, Weidolf L

Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes.

Drug Metab Dispos. 2000 Aug;28(8):966-72.

PubMed ID

10901708 [ View in PubMed

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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 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Omeprazole	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details