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Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations

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

Abstract

Objective

The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes.

Methods

Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases.

Results

Mean omeprazole AUC (0,∞) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose.

Conclusion

This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.

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References

  1. Wallmark B, Jaresten BM, Larsson H, Ryberg B, Brandstrom A, Fellenius E (1983) Differentiation among inhibitory actions of omeprazole, cimetidine, and SCN- on gastric acid secretion. Am J Physiol 245:G64–G71

    PubMed  CAS  Google Scholar 

  2. Howden CW (1991) Clinical pharmacology of omeprazole. Clin Pharmacokinet 20:38–49

    PubMed  CAS  Google Scholar 

  3. Maton PN (1991) Omeprazole. N Engl J Med 324:965–975

    Article  PubMed  CAS  Google Scholar 

  4. Lind T, Megraud F, Unge P, Bayerdorffer E, O’morain C, Spiller R, Veldhuyzen Van Zanten S, Bardhan KD, Hellblom M, Wrangstadh M, Zeijlon L, Cederberg C (1999) The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 116:248–253

    Article  PubMed  CAS  Google Scholar 

  5. Tytgat GN (1994) Review article: treatments that impact favourably upon the eradication of Helicobacter pylori and ulcer recurrence. Aliment Pharmacol Ther 8:359–368

    Article  PubMed  CAS  Google Scholar 

  6. Lind T, Veldhuyzen van Zanten S, Unge P, Spiller R, Bayerdorffer E, O’Morain C, Bardhan KD, Bradette M, Chiba N, Wrangstadh M, Cederberg C, Idstrom JP (1996) Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study. Helicobacter 1:138–144

    Article  PubMed  CAS  Google Scholar 

  7. 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 

  8. Andersson T, Miners JO, Veronese ME, Birkett DJ (1994) Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism. Br J Clin Pharmacol 37:597–604

    PubMed  CAS  Google Scholar 

  9. Kita T, Tanigawara Y, Aoyama N, Hohda T, Saijoh Y, Komada F, Sakaeda T, Okumura K, Sakai T, Kasuga M (2001) CYP2C19 genotype related effect of omeprazole on intragastric pH and antimicrobial stability. Pharm Res 18:615–621

    Article  PubMed  CAS  Google Scholar 

  10. Andersson T, Regardh CG, Lou YC, Zhang Y, Dahl ML, Bertilsson L (1992) Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects. Pharmacogenetics 2:25–31

    Article  PubMed  CAS  Google Scholar 

  11. Sohn DR, Kobayashi K, Chiba K, Lee KH, Shin SG, Ishizaki T (1992) Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4′-hydroxylation recruited from an Oriental population. J Pharmacol Exp Ther 262:1195–1202

    PubMed  CAS  Google Scholar 

  12. Chang M, Tybring G, Dahl ML, Gotharson E, Sagar M, Seensalu R, Bertilsson L (1995) Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4′-hydroxylation recruited from an Oriental population. Br J Clin Pharmacol 39:511–518

    PubMed  CAS  Google Scholar 

  13. 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 

  14. Andersson T, Cederberg C, Regardh CG, Skanberg I (1990) Pharmacokinetics of various single intravenous and oral doses of omeprazole. Eur J Clin Pharmacol 39:195–197

    Article  PubMed  CAS  Google Scholar 

  15. Regardh CG, Andersson T, Lagerstrom PO, Lundborg P, Skanberg I (1990) The pharmacokinetics of omeprazole in humans-a study of single intravenous and oral doses. Ther Drug Monit 12:163–172

    Article  PubMed  CAS  Google Scholar 

  16. 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 46:594–859

    PubMed  Google Scholar 

  17. Shimizu M, Uno T, Niioka T, Yasui-Furukori N, Takahata T, Sugawara S, 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 832:241–248

    Article  CAS  Google Scholar 

  18. Andersson T (1996) Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 31:9–28

    Article  PubMed  CAS  Google Scholar 

  19. Schwab M, Klotz U, Hofmann U, Schaeffeler E, Leodolter A, Malfertheiner P, Treiber G (2005) Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data. Clin Pharmacol Ther 78:627–634

    Article  PubMed  CAS  Google Scholar 

  20. Lapple F, von Richter O, Fromm MF, Richter T, Thon KP, Wisser H, Griese EU, Eichelbaum M, Kivisto KT (2003) Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics 13:565–575

    Article  PubMed  Google Scholar 

  21. Andersson T, Miners JO, Veronese ME, Birkett DJ (1994) Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism. Br J Clin Pharmacol 37:597–604

    PubMed  CAS  Google Scholar 

  22. Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS (1987) Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 80:1029–1036

    Article  PubMed  CAS  Google Scholar 

  23. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF (2001) Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol 364:551–557

    Article  PubMed  CAS  Google Scholar 

  24. Andersson T, Holmberg J, Rohss K, Walan A (1998) Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol 45:369–375

    Article  PubMed  CAS  Google Scholar 

  25. Yasuda S, Horai Y, Tomono Y, Nakai H, Yamato C, Manabe K, Kobayashi K, Chiba K, Ishizaki T (1995) Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther 58:143–154

    Article  PubMed  CAS  Google Scholar 

  26. Furuta T, Shirai N, Sugimoto M, Ohashi K, Ishizaki T (2004) Pharmacogenomics of proton pump inhibitors. Pharmacogenomics 5:181–202

    Article  PubMed  CAS  Google Scholar 

  27. Abelo A, Andersson TB, Antonsson M, Naudot AK, Skanberg I, Weidolf L (2000) Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 28:966–972

    PubMed  CAS  Google Scholar 

  28. Kanazawa H, Okada A, Higaki M, Yokota H, Mashige F, Nakahara K (2003) Stereospecific analysis of omeprazole in human plasma as a probe for CYP2C19 phenotype. J Pharm Biomed Anal 30:1817–1824

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We thank Dr. Tommy Andersson (Experimental Medicine, AstraZeneca LP, Wilmington, USA) for meaningful advice in the discussion section. This work was supported by the Japanese Research Foundation for Clinical Pharmacology.

Conflict of interest statement

The authors have no conflicts of interest in relation to this paper.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan

    Tsukasa Uno, Norio Yasui-Furukori & Tomonori Tateishi

  2. Department of Pharmacy, Hirosaki University Hospital, Hirosaki, 036-8562, Japan

    Takenori Niioka, Makoto Hayakari & Kazunobu Sugawara

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

    Norio Yasui-Furukori

  4. Department of Clinical Pharmacy, Aomori University School of Pharmacy, Aomori, Japan

    Kazunobu Sugawara

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  1. Tsukasa Uno
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  2. Takenori Niioka
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  3. Makoto Hayakari
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  4. Norio Yasui-Furukori
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Correspondence to Tsukasa Uno.

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Uno, T., Niioka, T., Hayakari, M. et al. Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations. Eur J Clin Pharmacol 63, 143–149 (2007). https://doi.org/10.1007/s00228-006-0251-7

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  • DOI: https://doi.org/10.1007/s00228-006-0251-7

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