Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes
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.
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).
After single IV administration of racemic omeprazole (20 mg), the mean area under the plasma concentration-time curve (AUC0-∞) 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 AUC0-∞ 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 AUC0-∞ of S(−)-5-hydroxyomeprazole was greater than that of R(+)-5-hydroxyomeprazole in the PMs.
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.
KEY WORDSCYP2C19 R(+)-5-hydroxyomeprazole R(+)-omeprazole S(−)-5-hydroxyomeprazole S(−)-omeprazole
area under the plasma concentration-time curve
maximum plasma concentration
homozygous extensive metabolizers
high-performance liquid chromatography
heterozygous extensive metabolizers
elimination rate constant
proton pump inhibitor
ACKNOWLEDGMENTS & DISCLOSURES
This works was supported by Grants-in-Aid for Scientific Research (no. 20590150) Tokyo, Japan.
- 2.Mohammad M, Amir HDJ, Ahmad S, Neda M, Farinaz T. A randomized controlled trial: efficacy and safety of azathromycin, ofloxacin, bismutu and omeprazole compared with amoxicillin, clarithromycin, bismuth, and omeprazole as second-line therapy in patients with Helicobacter pylori infection. Helicobacter. 2010;15:154–9.CrossRefGoogle Scholar
- 10.Ieiri I, Kubota T, Urae A, Kimura M, Wada Y, Mamiya K, et al. Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, C gamma P2C19m1 in exon 5 and C gamma P2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther. 1996;59:647–53.PubMedCrossRefGoogle Scholar
- 13.Hassan-Alin M, Andersson T, Niazi M, Röhss K. A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in helthy subjects. Eur J Clin Pharmacol. 2005;60:779–84.PubMedCrossRefGoogle Scholar