Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent

The Pharmacogenomics Journal volume 14, pages 151–159 (2014)Cite this article

Subjects

Abstract

Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20 mg oral dose of omeprazole on two occasions: with a single 600 mg efavirenz dose; and after a 17-day treatment with efavirenz (600 mg per day). DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by liquid chromatography/tandem mass spectrometry. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (P<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z . The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003; 306: 287–300.

    Article  CAS  PubMed  Google Scholar 

  2. Mutlib AE, Chen H, Nemeth GA, Markwalder JA, Seitz SP, Gan LS et al. Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz. Drug Metab Dispos 1999; 27: 1319–1333.

    CAS  PubMed  Google Scholar 

  3. Belanger AS, Caron P, Harvey M, Zimmerman PA, Mehlotra RK, Guillemette C . Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dispos 2009; 37: 1793–1796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K et al. Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics 2007; 8: 547–558.

    Article  CAS  PubMed  Google Scholar 

  5. Bae SK, Jeong YJ, Lee C, Liu KH . Identification of human UGT isoforms responsible for glucuronidation of efavirenz and its three hydroxy metabolites. Xenobiotica 41: 437–444.

    Article  CAS  PubMed  Google Scholar 

  6. Zhu M, Kaul S, Nandy P, Grasela DM, Pfister M . Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine. Antimicrob Agents Chemother 2009; 53: 2346–2353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ngaimisi E, Mugusi S, Minzi OM, Sasi P, Riedel KD, Suda A et al. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharmacol Ther 88: 676–684.

    Article  CAS  Google Scholar 

  8. Michaud V, Ogburn E, Thong N, Aregbe AO, Quigg TC, Flockhart DA et al. Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers. Clin Pharmacol Ther 2012; 91: 475–482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. von Moltke LL, Greenblatt DJ, Granda BW, Giancarlo GM, Duan SX, Daily JP et al. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol 2001; 41: 85–91.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Desta Z, Zhao X, Shin JG, Flockhart DA . Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41: 913–958.

    Article  CAS  PubMed  Google Scholar 

  13. Wang G, Lei HP, Li Z, Tan ZR, Guo D, Fan L et al. The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol 2009; 65: 281–285.

    Article  CAS  PubMed  Google Scholar 

  14. Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E . Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 2008; 83: 322–327.

    Article  CAS  PubMed  Google Scholar 

  15. Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman-Sundberg M, Eliasson E et al. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol 2008; 65: 767–774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J . Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol 2010; 69: 222–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121: 512–518.

    Article  CAS  PubMed  Google Scholar 

  18. Lee LS, Nafziger AN, Bertino Jr. JS . Evaluation of inhibitory drug interactions during drug development: genetic polymorphisms must be considered. Clin Pharmacol Ther 2005; 78: 1–6.

    Article  CAS  PubMed  Google Scholar 

  19. Wang LS, Zhu B, Abd El-Aty AM, Zhou G, Li Z, Wu J et al. The influence of St John's Wort on CYP2C19 activity with respect to genotype. J Clin Pharmacol 2004; 44: 577–581.

    Article  PubMed  Google Scholar 

  20. Kanebratt KP, Diczfalusy U, Backstrom T, Sparve E, Bredberg E, Bottiger Y et al. Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4beta-hydroxycholesterol. Clin Pharmacol Ther 2008; 84: 589–594.

    Article  CAS  PubMed  Google Scholar 

  21. Mihara K, Svensson US, Tybring G, Hai TN, Bertilsson L, Ashton M . Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19. Fundam Clin Pharmacol 1999; 13: 671–675.

    Article  CAS  PubMed  Google Scholar 

  22. Liu P, Foster G, Gandelman K, LaBadie RR, Allison MJ, Gutierrez MJ et al. Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects. Antimicrob Agents Chemother 2007; 51: 3617–3626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M et al. Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 2004; 319: 1322–1326.

    Article  CAS  PubMed  Google Scholar 

  24. Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 2005; 15: 1–5.

    Article  CAS  PubMed  Google Scholar 

  25. Cabrera SE, Santos D, Valverde MP, Dominguez-Gil A, Gonzalez F, Luna G et al. Influence of the cytochrome P450 2B6 genotype on population pharmacokinetics of efavirenz in human immunodeficiency virus patients. Antimicrob Agents Chemother 2009; 53: 2791–2798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lindfelt T, O'Brien J, Song JC, Patel R, Winslow DL . Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms. Ann Pharmacother 2010; 44: 1572–1578.

    Article  CAS  PubMed  Google Scholar 

  27. Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004; 18: 2391–2400.

    CAS  PubMed  Google Scholar 

  28. Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007; 320: 72–80.

    Article  CAS  PubMed  Google Scholar 

  29. Mouly S, Lown KS, Kornhauser D, Joseph JL, Fiske WD, Benedek IH et al. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther 2002; 72: 1–9.

    Article  CAS  PubMed  Google Scholar 

  30. Ngaimisi E, Mugusi S, Minzi OM, Sasi P, Riedel KD, Suda A et al. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharmacol Ther 2010; 88: 676–684.

    Article  CAS  PubMed  Google Scholar 

  31. Gonzalez HM, Romero EM, Peregrina AA, de J Chávez T, Escobar-Islas E, Lozano F et al. CYP2C19- and CYP3A4-dependent omeprazole metabolism in West Mexicans. J Clin Pharmacol 2003; 43: 1211–1215.

    Article  CAS  PubMed  Google Scholar 

  32. Isaza C, Henao J, Martinez JH, Sepulveda Arias JC, Beltran L . Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals. BMC Clin Pharmacol 2007; 7: 6.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Bottiger Y . Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4. Eur J Clin Pharmacol 2006; 62: 621–625.

    Article  PubMed  Google Scholar 

  36. Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM et al. St John’s wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther 2004; 75: 191–197.

    Article  CAS  PubMed  Google Scholar 

  37. Svensson US, Ashton M, Trinh NH, Bertilsson L, Dinh XH, Nguyen VH et al. Artemisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 1998; 64: 160–167.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rengelshausen J, Banfield M, Riedel KD, Burhenne J, Weiss J, Thomsen T et al. Opposite effects of short-term and long-term St John’s Wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 2005; 78: 25–33.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ et al. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 68: 598–604.

    Article  CAS  PubMed  Google Scholar 

  43. Matheny CJ, Ali RY, Yang X, Pollack GM . Effect of prototypical inducing agents on P-glycoprotein and CYP3A expression in mouse tissues. Drug Metab Dispos 2004; 32: 1008–1014.

    CAS  PubMed  Google Scholar 

  44. Tannergren C, Engman H, Knutson L, Hedeland M, Bondesson U, Lennernas H . St John’s wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism. Clin Pharmacol Ther 2004; 75: 298–309.

    Article  CAS  PubMed  Google Scholar 

  45. Habtewold A, Amogne W, Makonnen E, Yimer G, Nylen H, Riedel KD et al. Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients. Pharmacogenomics J, advance online publication, 23 October 2012; doi:10.1038/tpj.2012.46 (e-pub ahead of print).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Sugimoto K, Uno T, Tateishi T . Effects of the CYP3A5 genotype on omeprazole sulfoxidation in CYP2C19 PMs. Eur J Clin Pharmacol 2008; 64: 583–587.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The project described here was supported by Award Number R01GM078501, 3R01GM078501-04S1, R56 grant (2R56GM067308-09A1) from the National Institute of General Medical Sciences, National Institutes of Health (Bethesda, MD), and by Award Number M01-RR00750 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Veronique Michaud is the recipient of a fellowship from the Canadian Institutes of Health Research and winner of the Bisby award.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA

    V Michaud, Y Kreutz, T Skaar, E Ogburn, N Thong, D A Flockhart & Z Desta

Authors
  1. V Michaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Kreutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Skaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Ogburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Thong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D A Flockhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z Desta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z Desta.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michaud, V., Kreutz, Y., Skaar, T. et al. Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent. Pharmacogenomics J 14, 151–159 (2014). https://doi.org/10.1038/tpj.2013.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2013.17

Keywords

Search

Advanced search

Quick links