Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects.
Stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite were studied in five poor metabolizers and five extensive metabolizers of S-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separate enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 hours after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+)-omeprazole was larger and that of the 5-hydroxy metabolite of this enantiomer was smaller than the AUC(0-8) values in extensive metabolizers (p < 0.001). The mean AUC(0-8) of the (-)-enantiomer of omeprazole was also higher in poor metabolizers than in extensive metabolizers, but only 3.1-fold compared with 7.5-fold for (+)-omeprazole. The rate of formation of the hydroxy metabolite from (-)-omeprazole was low and not significantly different in poor and extensive metabolizers. These results show that (+)-omeprazole is to a major extent hydroxylated by CYP2C19. Also (-)-omeprazole may partly be metabolized by this enzyme but is mainly metabolized by another enzyme, presumably CYP3A4, to the achiral sulfone metabolite. The plasma concentration ratio of omeprazole to 5-hydroxyomeprazole obtained 3 hours after the drug intake has been used to distinguish between extensive and poor metabolizer phenotypes. With use of the ratio between the (+)-enantiomers of the parent drug and the metabolite, a better discrimination between phenotypes was obtained. The ratio between the (-)-enantiomers also separated the phenotypes but was less discriminatory. For the future, measurement of total concentrations will suffice for phenotyping.
Tybring
G
G
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
Böttiger
Y
Y
Widén
J
J
Bertilsson
L
L
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007536:Isomerism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009853:Omeprazole / Q000031:analogs & derivatives / Q000378:metabolism*; D013548:Sweden
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; C049963:5-hydroxymethylomeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole