Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms.
OBJECTIVE
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.
Levin
Mark-David
MD
Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands. levin@xs4all.nl
den Hollander
Jan G
JG
van der Holt
Bronno
B
Rijnders
Bart J
BJ
van Vliet
Martin
M
Sonneveld
Pieter
P
van Schaik
Ron H N
RH
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects*; D012189:Retrospective Studies; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects*; D065819:Voriconazole