Hydroxylation of R (+)- and S (−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes

BSTRACT Purpose To elucidate the stereoselective pharmacokinetics of omeprazole enantiomers and their metabolites after racemic IV dosing because there is little information about the stereoselective metabolism of omeprazole in in vivo study. Methods Seventeen subjects were classified into three CYP2C19 groups based on their genotypes: homozygous extensive metabolizers (hmEMs; n = 5), heterozygous EMs (htEMs; n = 7) and poor metabolizers (PMs; n = 5). Results After single IV administration of racemic omeprazole (20 mg), the mean area under the plasma concentration-time curve (AUC 0-∞ ) of R (+)-omeprazole in PMs was significantly higher than that in hmEMs and htEMs, while that of S (−)-omeprazole was no significance among three genotypes because of a wide inter-individual variability. In addition, although the AUC 0-∞ of R (+)-5-hydroxyomeprazole were determined among three genotypes, the that of S (−)-5-hydroxyomeprazole was undetectable in the hmEMs and barely detectable in the htEMs. Conversly, the AUC 0-∞ of S (−)-5-hydroxyomeprazole was greater than that of R (+)-5-hydroxyomeprazole in the PMs. Conclusions These data therefore suggest that, for EMs, the CYP2C19-mediated formation from R (+)-enantiomer is a 5-hydroxy-metabolite, while that from S (−)-enantiomer may be a minor metabolite. Thus, the in vivo disposition of S (−)- and R (+)-omeprazole after racemic dosing may be different among the CYP2C19 genotypes.