Skip to main content
The Yale Journal of Biology and Medicine logoLink to The Yale Journal of Biology and Medicine
. 1996 May-Jun;69(3):203–209.

Interaction of proton pump inhibitors with cytochromes P450: consequences for drug interactions.

U A Meyer 1
PMCID: PMC2589004  PMID: 9165689

Abstract

Omeprazole, lansoprazole and pantoprazole are metabolized by several human cytochromes P450, most prominently by CYP2C19 and CYP3A4. Only pantoprazole is also metabolized by a sulfotransferase. Differences in the quantitative contribution of these enzymes and in the relative affinities of the substrates explain some of the observed interactions with carbamazepin, diazepam, phenytoin and theophylline and of the impact of the CYP2C19 (mephenytoin) genetic polymorphism. Of these drugs, pantoprazole has the lowest potential for interactions, both in vitro and in human volunteer studies.

Full text

PDF
203

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersson T., Cederberg C., Edvardsson G., Heggelund A., Lundborg P. Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. Clin Pharmacol Ther. 1990 Jan;47(1):79–85. doi: 10.1038/clpt.1990.12. [DOI] [PubMed] [Google Scholar]
  2. Andersson T., Miners J. O., Veronese M. E., Birkett D. J. Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism. Br J Clin Pharmacol. 1994 Jun;37(6):597–604. doi: 10.1111/j.1365-2125.1994.tb04310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Andersson T., Miners J. O., Veronese M. E., Tassaneeyakul W., Tassaneeyakul W., Meyer U. A., Birkett D. J. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol. 1993 Dec;36(6):521–530. doi: 10.1111/j.1365-2125.1993.tb00410.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Andersson T., Regårdh C. G., Dahl-Puustinen M. L., Bertilsson L. Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit. 1990 Jul;12(4):415–416. doi: 10.1097/00007691-199007000-00020. [DOI] [PubMed] [Google Scholar]
  5. Andersson T., Regårdh C. G., Lou Y. C., Zhang Y., Dahl M. L., Bertilsson L. Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects. Pharmacogenetics. 1992 Feb;2(1):25–31. doi: 10.1097/00008571-199202000-00005. [DOI] [PubMed] [Google Scholar]
  6. Balian J. D., Sukhova N., Harris J. W., Hewett J., Pickle L., Goldstein J. A., Woosley R. L., Flockhart D. A. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther. 1995 Jun;57(6):662–669. doi: 10.1016/0009-9236(95)90229-5. [DOI] [PubMed] [Google Scholar]
  7. Buchthal J., Grund K. E., Buchmann A., Schrenk D., Beaune P., Bock K. W. Induction of cytochrome P4501A by smoking or omeprazole in comparison with UDP-glucuronosyltransferase in biopsies of human duodenal mucosa. Eur J Clin Pharmacol. 1995;47(5):431–435. doi: 10.1007/BF00196857. [DOI] [PubMed] [Google Scholar]
  8. Caraco Y., Tateishi T., Wood A. J. Interethnic difference in omeprazole's inhibition of diazepam metabolism. Clin Pharmacol Ther. 1995 Jul;58(1):62–72. doi: 10.1016/0009-9236(95)90073-X. [DOI] [PubMed] [Google Scholar]
  9. Chang M., Tybring G., Dahl M. L., Götharson E., Sagar M., Seensalu R., Bertilsson L. Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol. 1995 May;39(5):511–518. doi: 10.1111/j.1365-2125.1995.tb04488.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chiba K., Kobayashi K., Manabe K., Tani M., Kamataki T., Ishizaki T. Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephenytoin 4'-hydroxylation. J Pharmacol Exp Ther. 1993 Jul;266(1):52–59. [PubMed] [Google Scholar]
  11. Curi-Pedrosa R., Daujat M., Pichard L., Ourlin J. C., Clair P., Gervot L., Lesca P., Domergue J., Joyeux H., Fourtanier G. Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture. J Pharmacol Exp Ther. 1994 Apr;269(1):384–392. [PubMed] [Google Scholar]
  12. Daujat M., Peryt B., Lesca P., Fourtanier G., Domergue J., Maurel P. Omeprazole, an inducer of human CYP1A1 and 1A2, is not a ligand for the Ah receptor. Biochem Biophys Res Commun. 1992 Oct 30;188(2):820–825. doi: 10.1016/0006-291x(92)91130-i. [DOI] [PubMed] [Google Scholar]
  13. De Morais S. M., Wilkinson G. R., Blaisdell J., Meyer U. A., Nakamura K., Goldstein J. A. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994 Oct;46(4):594–598. [PubMed] [Google Scholar]
  14. Diaz D., Fabre I., Daujat M., Saint Aubert B., Bories P., Michel H., Maurel P. Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology. 1990 Sep;99(3):737–747. doi: 10.1016/0016-5085(90)90963-2. [DOI] [PubMed] [Google Scholar]
  15. Gugler R., Jensen J. C. Omeprazole inhibits oxidative drug metabolism. Studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro. Gastroenterology. 1985 Dec;89(6):1235–1241. [PubMed] [Google Scholar]
  16. Huber R., Kohl B., Sachs G., Senn-Bilfinger J., Simon W. A., Sturm E. Review article: the continuing development of proton pump inhibitors with particular reference to pantoprazole. Aliment Pharmacol Ther. 1995 Aug;9(4):363–378. doi: 10.1111/j.1365-2036.1995.tb00394.x. [DOI] [PubMed] [Google Scholar]
  17. Ishizaki T., Sohn D. R., Kobayashi K., Chiba K., Lee K. H., Shin S. G., Andersson T., Regårdh C. G., Lou Y. C., Zhang Y. Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals. Ther Drug Monit. 1994 Apr;16(2):214–215. doi: 10.1097/00007691-199404000-00018. [DOI] [PubMed] [Google Scholar]
  18. Kokufu T., Ihara N., Sugioka N., Koyama H., Ohta T., Mori S., Nakajima K. Effects of lansoprazole on pharmacokinetics and metabolism of theophylline. Eur J Clin Pharmacol. 1995;48(5):391–395. doi: 10.1007/BF00194956. [DOI] [PubMed] [Google Scholar]
  19. Kromer W. Similarities and differences in the properties of substituted benzimidazoles: a comparison between pantoprazole and related compounds. Digestion. 1995;56(6):443–454. doi: 10.1159/000201275. [DOI] [PubMed] [Google Scholar]
  20. Landes B. D., Petite J. P., Flouvat B. Clinical pharmacokinetics of lansoprazole. Clin Pharmacokinet. 1995 Jun;28(6):458–470. doi: 10.2165/00003088-199528060-00004. [DOI] [PubMed] [Google Scholar]
  21. Lefebvre R. A., Flouvat B., Karolac-Tamisier S., Moerman E., Van Ganse E. Influence of lansoprazole treatment on diazepam plasma concentrations. Clin Pharmacol Ther. 1992 Nov;52(5):458–463. doi: 10.1038/clpt.1992.172. [DOI] [PubMed] [Google Scholar]
  22. McDonnell W. M., Scheiman J. M., Traber P. G. Induction of cytochrome P450IA genes (CYP1A) by omeprazole in the human alimentary tract. Gastroenterology. 1992 Nov;103(5):1509–1516. doi: 10.1016/0016-5085(92)91171-y. [DOI] [PubMed] [Google Scholar]
  23. Meyer U. A., Zanger U. M. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol. 1997;37:269–296. doi: 10.1146/annurev.pharmtox.37.1.269. [DOI] [PubMed] [Google Scholar]
  24. Pichard L., Curi-Pedrosa R., Bonfils C., Jacqz-Aigrain E., Domergue J., Joyeux H., Cosme J., Guengerich F. P., Maurel P. Oxidative metabolism of lansoprazole by human liver cytochromes P450. Mol Pharmacol. 1995 Feb;47(2):410–418. [PubMed] [Google Scholar]
  25. Quattrochi L. C., Tukey R. H. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1A1 gene. Mol Pharmacol. 1993 Apr;43(4):504–508. [PubMed] [Google Scholar]
  26. Rost K. L., Brösicke H., Heinemeyer G., Roots I. Specific and dose-dependent enzyme induction by omeprazole in human beings. Hepatology. 1994 Nov;20(5):1204–1212. [PubMed] [Google Scholar]
  27. Rost K. L., Roots I. Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: coincidence with plasma clearance and breath test. Clin Pharmacol Ther. 1994 Apr;55(4):402–411. doi: 10.1038/clpt.1994.49. [DOI] [PubMed] [Google Scholar]
  28. Sohn D. R., Kobayashi K., Chiba K., Lee K. H., Shin S. G., Ishizaki T. 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. 1992 Sep;262(3):1195–1202. [PubMed] [Google Scholar]
  29. Steinijans V. W., Huber R., Hartmann M., Zech K., Bliesath H., Wurst W., Radtke H. W. Lack of pantoprazole drug interactions in man. Int J Clin Pharmacol Ther. 1994 Aug;32(8):385–399. [PubMed] [Google Scholar]
  30. Tucker G. T. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther. 1994;8 (Suppl 1):33–38. doi: 10.1111/j.1365-2036.1994.tb00233.x. [DOI] [PubMed] [Google Scholar]
  31. Wilde M. I., McTavish D. Omeprazole. An update of its pharmacology and therapeutic use in acid-related disorders. Drugs. 1994 Jul;48(1):91–132. doi: 10.2165/00003495-199448010-00008. [DOI] [PubMed] [Google Scholar]
  32. de Morais S. M., Wilkinson G. R., Blaisdell J., Nakamura K., Meyer U. A., Goldstein J. A. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994 Jun 3;269(22):15419–15422. [PubMed] [Google Scholar]

Articles from The Yale Journal of Biology and Medicine are provided here courtesy of Yale Journal of Biology and Medicine

RESOURCES