Enantiomer/enantiomer interactions between the S- and R- isomers of omeprazole in human cytochrome P450 enzymes: major role of CYP2C19 and CYP3A4.
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.
Li
Xue-Qing
XQ
DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Sweden. xueqing.li@astrazeneca.com
Weidolf
Lars
L
Simonsson
Roger
R
Andersson
Tommy B
TB
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009853:Omeprazole / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole