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JAC Advance Access published online on September 7, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm330
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms

Mark-David Levin1,*, Jan G. den Hollander2, Bronno van der Holt3, Bart J. Rijnders4, Martin van Vliet5, Pieter Sonneveld6 and Ron H. N. van Schaik5

1 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands 2 Department of Internal Medicine, MCRZ, Rotterdam, The Netherlands 3 Department of Trials and Statistics, Erasmus MC—Daniel den Hoed Cancer Center, Rotterdam, The Netherlands 4 Department of Internal Medicine, Section of Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands 5 Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands 6 Department of Hematology, Erasmus MC, Rotterdam, The Netherlands

Received 25 February 2007; returned 3 June 2007; revised 12 July 2007; accepted 6 August 2007

* Correspondence address. Department of Internal Medicine, Albert Schweitzer Hospital, Albert Schweitzerplaats 25, 3318 AT Dordrecht, The Netherlands. Tel: +31-78-654-1111; Fax: +31-78-652-3377; E-mail: levin{at}xs4all.nl

Objectives: Voriconazole, like all other antifungals of the azole group, is potentially hepatotoxic. A large interpatient variability of liver enzyme elevations during oral or intravenous (iv) voriconazole administration is observed. This interpatient variability may be explained by differences in voriconazole metabolism because of cytochrome P450 polymorphisms. We examined the relationship between cytochrome P450 polymorphisms and hepatotoxicity in immunocompromised patients predominantly receiving oral formulations of voriconazole.

Methods: In a single institution retrospective study of 86 immunocompromised patients receiving oral (n = 74) or iv (n = 12) voriconazole, we studied the influence of cytochrome P450 polymorphisms (CYP2C19, CYP2C9 and CYP3A5) on the maximum bilirubin and serum liver enzyme levels [alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), serum aspartate aminotransferase and serum alanine aminotransferase] and their respective common toxicity criteria scores (CTC-scores).

Results: Median serum bilirubin as well as the level of all other liver enzymes increased during voriconazole treatment. A decline in CTC-score was observed in zero (0%) to six (7%) patients; an increase in CTC-score was demonstrated in 36 (42%) to 54 (63%) patients. No statistically significant differences in maximum value or maximum increase of liver enzymes or CTC-score in relation to cytochrome P450 polymorphisms were observed. Only a trend towards higher maximum CTC-score of GGT for wild-type of CYP2C9 was observed (P = 0.046).

Conclusions: No significant relationship between CYP2C9, CYP2C19 or CYP3A5 polymorphisms and serum liver enzyme levels was observed in patients treated with voriconazole.

Key Words: liver , leukaemia , transplantation , pharmacokinetics


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