Skip to main content

Advertisement

SpringerLink
Log in

The Clinical Significance of Azole Antifungals’ Effects on the Liver and Transaminase Levels

  • Pharmacology and Pharmacodynamics of Antifungal Agents (P Gubbins, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Various case reports have been published regarding the incidence of hepatotoxicity and the triazoles. To date, of the more commonly used triazoles, voriconazole has been liked to the highest incidence of transaminase elevations followed by posaconazole, fluconazole, and itraconazole, respectively. Discontinuation of each of the drugs has been shown to resolve the increase of transaminase levels; however, no clear guidance has been suggested on as to when discontinuation of therapy is warranted. Close monitoring particularly patients of Asian decent, underlying liver disease, bone marrow, or lung transplant may be prudent as well as target drug monitoring (TDM) for posaconazole and voriconazole to help assess the necessity of alteration or discontinuation of therapy.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. http://livertox.nlm.nih.gov/Fluconazole.htm Accessed 3/25/2015.

  2. http://livertox.nih.gov/Itraconazole.htm Accessed 3/27/2015.

  3. http://livertox.nlm.nih.gov/Posaconazole.htm Accessed 3/31/2015.

  4. http://livertox.nlm.nih.gov/Voriconazole.htm Accessed 4/10/2015.

  5. Diflucan® [package insert]. New York, NY. Pfizer. 2013.

  6. Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal medications in bone marrow transplant recipients. Clin Infect Dis. 2005;41:301–7.

    Article  CAS  PubMed  Google Scholar 

  7. Song J, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig Drugs. 2005;6:170–7.

    PubMed  Google Scholar 

  8. Reuben A, Koch DG, Lee WM, Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Girois SB, Chapuis F, Decullier E, Revol BG. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2006;25:138–49.

    Article  CAS  PubMed  Google Scholar 

  10. Wang JL, Chang CH, Young-Xu Y, Chan KA. Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob Agents Chemother. 2010;54:2409–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Moseley RH. Antifungal agents. Antibacterial and antifungal agents. In: Kaplowitz N, DeLeve LD, editors. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier; 2013. p. 470–81.

    Google Scholar 

  12. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 Accessed 3/27/2015

  13. Somchit N, Norshahida AR, Hasiah AH, Zuraini A, et al. Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study. Hum Exp Toxicol. 2004;23:519–25.

    Article  CAS  PubMed  Google Scholar 

  14. Posaconazole. Clinical pharmacology; Gold Standard Multimedia. Accessed March 29, 2015

  15. Raschi E, Poluzzi E, Koci A, Caraceni P, et al. Assessing liver injury associated with antimycotics: concise literature review and clues from data mining of the FAERS database. World J Hepatol. 2014;6(8):601–12. A compiled review from the FDA Adverse Events Reporting System showing that all triazole antifungals have been associated with clinical significant liver toxicity.

    PubMed Central  PubMed  Google Scholar 

  16. Foo H, Gottlieb T. Lack of cross-hepatotoxicity between voriconazole and posaconazole. Clin Infect Dis. 2007;45:803–5.

    Article  PubMed  Google Scholar 

  17. Pfizer Inc. Label: voriconazole for injection, tablets, oral suspension: LAB-0271-22.0; revised 2010 June.

  18. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet. 2006;45(7):649–63.

    Article  CAS  PubMed  Google Scholar 

  19. Levin MD, den Hollander JG, van der Holt B, et al. Hepatotoxicity of oral and intravenous voriconazole in relations to cytochrome P450 polymorphisms. J Antimicrob Chemother. 2007;60:1104–7.

    Article  CAS  PubMed  Google Scholar 

  20. den Hollander JG, van Arkel C, Rijnders BJ, et al. Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections. J Antimicrob Chemother. 2006;57:1248–50.

    Article  Google Scholar 

  21. Gorski E, Esterly JS, Postelnick M, et al. Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections. Antimicrob Agents Chemother. 2011;55(1):184–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Alffenaar JWC, van Assen S, de Monchy JGR, et al. Intravenous voriconazole after toxic oral administration. Antimicrob Agents Chemother. 2010;54(6):2741–2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Luong ML, Hosseini-Moghaddam SM, Singer LG, et al. Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients. Am J Transplant. 2012;12(7):1929–35.

    Article  CAS  PubMed  Google Scholar 

  24. Belaiche S, Roustit M, Bedouch P, et al. Management of voriconazole hepatotoxicity in a lung transplant patient. Transpl Infect Dis. 2011;13:309–11.

    Article  CAS  PubMed  Google Scholar 

  25. Matsumoto K, Ikawa K, Abematsu K, et al. Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents. 2009;34:91–4.

    Article  CAS  PubMed  Google Scholar 

  26. Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab. 2003;31:540–7.

    Article  CAS  Google Scholar 

  27. Wang T, Zhu H, Sun J, et al. Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections. Int J Antimicrob Agents. 2014;44:436–42. This study helped determine the optimum voriconazole target concentration and attempted to identify a dose-adjustment strategy for voriconazole according to CYP2C19 polymorphism.

    Article  CAS  PubMed  Google Scholar 

  28. Lutsar I, Hodges MR, Tomaszewski K, et al. Safety of voriconazole and dose individualization [letter]. Clin Infect Dis. 2003;36(8):1087–8.

    Article  PubMed  Google Scholar 

  29. Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol. 2006;46:235–43.

    Article  CAS  PubMed  Google Scholar 

  30. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46:201–11.

    Article  CAS  PubMed  Google Scholar 

  31. Mitsani D, Nguyen MH, Shields RK, et al. Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity. Antimicrob Agents Chemother. 2012;56(5):2371–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Chu HY, Jain R, Xie H, et al. Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events. BMC Infect Dis. 2013;13:105.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Suzuki Y, Tokimatsu I, Sato Y, et al. Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin Chim Acta. 2013;424:119–22.

    Article  CAS  PubMed  Google Scholar 

  34. Dolton MJ, McLachlan AJ. Voriconazole pharmacokinetics and exposure–response relationships: assessing the links between exposure, efficacy and toxicity. Int J Antimicrob Agents. 2014;44:183–93. Excellent review providing a critical analysis on voriconazole pharmacokinetics, exposure response relationships and toxicity.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Viktorija O. Barr, Elizabeth G. Zdyb, and Michael Postelnick declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA

    Viktorija O. Barr, Elizabeth G. Zdyb & Michael Postelnick

  2. Department of Pharmacy Practice, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    Viktorija O. Barr

  3. Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA

    Elizabeth G. Zdyb

Authors
  1. Viktorija O. Barr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth G. Zdyb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Postelnick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Postelnick.

Additional information

This article is part of the Topical Collection on Pharmacology and Pharmacodynamics of Antifungal Agents

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barr, V.O., Zdyb, E.G. & Postelnick, M. The Clinical Significance of Azole Antifungals’ Effects on the Liver and Transaminase Levels. Curr Fungal Infect Rep 9, 190–195 (2015). https://doi.org/10.1007/s12281-015-0226-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-015-0226-1

Keywords

Search

Navigation