Skip to main content
SpringerLink
Log in

The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals.

Methods

Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column.

Results

Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI.

Conclusion

Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA (1994) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46:594–598

    PubMed  Google Scholar 

  2. Andersson T, Weidolf L (2008) Stereoselective disposition of proton pump inhibitors. Clin Drug Investig 28:263–279

    Article  PubMed  CAS  Google Scholar 

  3. Andersson T, Hassan-Alin M, Hasselgren G, Röhss K, Weidolf L (2001) Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet 40:411–426

    Article  PubMed  CAS  Google Scholar 

  4. Padol S, Yuan Y, Thabane M, Padol IT, Hunt RH (2006) The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta- analysis. Am J Gastroenterol 101:1467–1475

    Article  PubMed  CAS  Google Scholar 

  5. Furuta T, Shirai N, Kodaira M, Sugimoto M, Nogaki A, Kuriyama S, Iwaizumi M, Yamade M, Terakawa I, Ohashi K, Ishizaki T, Hishida A (2007) Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther 81:521–528

    Article  PubMed  CAS  Google Scholar 

  6. Furuta T, Shirai N, Takashima M, Xiao F, Hanai H, Sugimura H, Ohashi K, Ishizaki T, Kaneko E (2001) Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69:158–168

    Article  PubMed  CAS  Google Scholar 

  7. Schwab M, Schaeffeler E, Klotz U, Treiber G (2004) CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori. Clin Pharmacol Ther 76:201–209

    Article  PubMed  CAS  Google Scholar 

  8. Olbe L, Carlsson E, Lindberg P (2003) A proton-pump inhibitor expedition: The case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2:132–139

    Article  PubMed  CAS  Google Scholar 

  9. Mohammad M, Amir HDJ, Ahmad S, Neda M, Farinaz T (2010) 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 15:154–159

    Article  Google Scholar 

  10. Ogawa R, Echizen H (2010) Drug-drug interaction profiles of proton pump inhibitors. Clin Pharmacokinet 1:509–533

    Article  Google Scholar 

  11. Chiba K, Kobayashi K, Manabe K, Tani M, Kamataki T, Ishizaki T (1993) Oxidative metabolism of omeprazole in human liver microsomes: Cosegregation with S-mephenytoin 4′-hydroxylation. J Pharmacol Exp Ther 266:52–59

    PubMed  CAS  Google Scholar 

  12. Andersson T, Miners JO, Veronese ME, Birkett DJ (1994) Identification of human liver cytochrome P450 isoform mediating secondary omeprazole metabolism. Br J Clin Pharmacol 35:597–604

    Article  Google Scholar 

  13. Äbelö A, Andersson T, Antonsson M, Naudot AK, Skanberg I, Weidolf L (2000) Stereoselective metabolism of omeprazole by human cytochrome P450 enzyme. Drug Metab Dispos 28:966–972

    PubMed  Google Scholar 

  14. Uno T, Niioka T, Hayakari M, Yasui-Furukori N, Sugawara K, Tateishi T (2007) Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations. Eur J Clin Pharmacol 63:143–149

    Article  PubMed  CAS  Google Scholar 

  15. Shimizu M, Uno T, Niioka T, Yasui-Furukori N, Takahata T, Sugawara K, Tateishi T (2006) Sensitive determination of omeprazole and its two main metabolites in human plasma by column-switching high-performance liquid chromatography: application to pharmacokinetic study in relation to CYP2C19 genotypes. J Chromatogr B Analyt Technol Biomed Life Sci 832:241–248

    Article  PubMed  CAS  Google Scholar 

  16. Ieiri I, Kubota T, Urae A, Kimura M, Wada Y, Mamiya K, Yoshioka S, Irie S, Amamoto T, Nakamura K, Nakano S, Higuchi S (1996) 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 59:647–653

    Article  PubMed  CAS  Google Scholar 

  17. Kimura M, Ieiri I, Wada Y, Mamiya K, Urae A, Iimori E, Sakai T, Otsubo K, Higuchi S (1999) Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy. Br J Clin Pharmacol 47:115–119

    Article  PubMed  CAS  Google Scholar 

  18. Niioka T, Uno T, Sugimoto K, Sugawara K, Hayakari M, Tateishi T (2007) Estimation of CYP2C19 activity by the omeprazole hydroxylation index at a single point in time after intravenous and oral administration. Eur J Clin Pharmacol 63:1031–1038

    Article  PubMed  CAS  Google Scholar 

  19. Rosemary J, Adithan C, Padmaja N, Shashindran CH, Gerard N, Krishnamoorthy R (2005) The effect of the CYP2C19 genotype on the hydroxylation index of omeprazole in South Indians. Eur J Clin Pharmacol 61:19–23

    Article  PubMed  CAS  Google Scholar 

  20. Yin OQ, Tomlinson B, Chow AH, Waye MM, Chow MS (2004) Omeprazole as a CYP2C19 marker in Chinese subjects: assessment of its gene-dose effect and intrasubject variability. J Clin Pharmacol 44:582–589

    Article  PubMed  CAS  Google Scholar 

  21. Shiohira H, Yasui-Furukori N, Yamada S, Tateishi T, Akamine Y, Uno T (2012) Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes. Pharm Res 29:2310–2316

    Article  PubMed  CAS  Google Scholar 

  22. Zhou HH, Anthony LB, Wood AJ, Wilkinson GR (1990) Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Br J Clin Pharmacol 30:471–475

    Article  PubMed  CAS  Google Scholar 

  23. Feng HJ, Huang SL, Wang W, Zhou HH (1998) The induction effect of rifampicin on activity of mephenytoin 4′-hydroxylase related to M1 mutation of CYP2C19 and gene dose. Br J Clin Pharmacol 45:27–29

    Article  PubMed  CAS  Google Scholar 

  24. Zhou HH (2001) CYP2C19 genotype determines enzyme activity and inducibility of S-mephenytoin hydroxylase. Clin Chim Acta 313:203–208

    Article  PubMed  CAS  Google Scholar 

  25. Wedlund PJ, Aslanian WS, Jacqz E, McAllister CB, Branch RA, Wilkinson GR (1985) Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. J Pharmacol Exp Ther 234:662–669

    PubMed  CAS  Google Scholar 

  26. Sugimoto K, Uno T, Yamazaki H, Tateishi T (2008) Limited frequency of the CYP2C19*17 allele and its minor role in a Japanese population. Br J Clin Pharmacol 65:437–439

    Article  PubMed  CAS  Google Scholar 

  27. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113

    Article  PubMed  CAS  Google Scholar 

  28. Shiohira H, Yasui-Furukori N, Tateishi T, Uno T (2011) Chiral assay of omeprazole and metabolites and its application to a pharmacokinetics related to CYP2C19 genotypes. J Chromatogr B Analyt Technol Biomed Life Sci 879:2465–2470

    Article  PubMed  CAS  Google Scholar 

  29. Tybring G, Böttiger Y, Widén J, Bertilsson L (1997) Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 62:129–137

    Article  PubMed  CAS  Google Scholar 

  30. Yasui-Furukori N, Takahata T, Nakagami T, Yoshiya G, Inoue Y, Kaneko S, Tateishi T (2004) Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes. Br J Clin Pharmacol 57:487–494

    Article  PubMed  CAS  Google Scholar 

  31. Li X, Weidolf L, Simonsson R, Andersson TB (2005) Enantiomer/Enantiomer interaction between the S- and R-isomers of omeprazole in human cytochrome P450 enzymes: major role of CYP2C19 and CYP3A4. J Pharmacol Exp Ther 315:777–787

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research (No. 20590150) Tokyo, Japan.

Conflict of interest statement

None

Author information

Authors and Affiliations

  1. Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa, 903-0215, Japan

    Satoshi Yamada, Hideo Shiohira, Yumiko Akamine & Tsukasa Uno

  2. Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan

    Norio Yasui-Furukori

  3. Pharmaceuticals and Medical Devices Agency, Tokyo, Japan

    Tomonori Tateishi

Authors
  1. Satoshi Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideo Shiohira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norio Yasui-Furukori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomonori Tateishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yumiko Akamine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tsukasa Uno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsukasa Uno.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamada, S., Shiohira, H., Yasui-Furukori, N. et al. The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers. Eur J Clin Pharmacol 69, 1423–1428 (2013). https://doi.org/10.1007/s00228-013-1480-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-013-1480-1

Keywords

Search

Navigation