Enantiomer/enantiomer interactions between the S- and R- isomers of omeprazole in human cytochrome P450 enzymes: major role of CYP2C19 and CYP3A4.
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Li XQ, Weidolf L, Simonsson R, Andersson TB
Enantiomer/enantiomer interactions between the S- and R- isomers of omeprazole in human cytochrome P450 enzymes: major role of CYP2C19 and CYP3A4.
J Pharmacol Exp Ther. 2005 Nov;315(2):777-87. Epub 2005 Aug 10.
- PubMed ID
- 16093273 [ View in PubMed]
- Abstract
We investigated the enzyme kinetic basis for the stereoselective disposition of R- and S-omeprazole (OME) and racemic OME in human liver microsomes. OME is primarily metabolized by the hepatic cytochrome P450 enzyme system (CYP2C19 and 3A4). The metabolism of each enantiomer and pseudoracemic OME was studied using unlabeled and (13)C(7)-labeled enantiomers. The enantiomers inhibited each other's metabolism competitively in human liver microsomes and in recombinant CYP2C19 and 3A4. The results obtained with the individual enantiomers allowed successful prediction of the enzyme kinetics for the pseudoracemate. The intrinsic clearance of each enantiomer in a pseudoracemic mixture remained the same as those of the individually incubated enantiomers, although K(m) and V(max) decreased. In the pseudoracemate, the relative contribution of CYP2C19 and 3A4 to 5-hydroxylation and 5'-O-demethylation of R-OME was comparable to that obtained for the incubation of R-OME alone. For S-OME, however, the presence of its antipode greatly increased the contribution of CYP3A4, with increasing concentrations, compared with that obtained when incubating S-OME alone. The results of our in vitro study clearly show metabolic interactions between the OME enantiomers, which may also occur in vivo. Because the enantiomers of OME produce similar pharmacological effects, the enantiomer interactions should not significantly affect the pharmacodynamics. On the other hand, the use of the S-enantiomer results in less complex enzyme kinetics than those of the racemate; thus, the outcome of its clinical use is more predictable.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Omeprazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Omeprazole Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails