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

Abstract

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 5 74) or iv (n 5 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 5 0.046).Conclusions: No significant relationship between CYP2C9, CYP2C19 or CYP3A5 polymorphisms and serum liver enzyme levels was observed in patients treated with voriconazole.

Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection

“…Nevertheless, a comparison of the data in the literature led an FDA advisory committee to conclude that in severely ill populations, the risk of hepatotoxic reactions associated with voriconazole use is not greater than that associated with the use of other antifungal agents (61). The liver toxicity caused by voriconazole may be attributed to the dosing regimens used, the serum drug concentration, or cytochrome P450 polymorphisms (15,17,43,45). Several researchers suggested that voriconazole therapeutic drug monitoring may improve treatment efficacy and safety among those with a higher risk of liver toxicity (40,45,48,58).…”

Cytotoxicity of Voriconazole on Cultured Human Corneal Endothelial Cells

“…The drug is, although infrequently, reported to be associated with clinically significant hepatotoxicity, mainly due to the fact that it is extensively metabolized by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4 (6,14,32). However, studies have shown that voriconazole toxicity has no relationship with CYP 2C19 status, although the (3,20). Rash and photosensitivity are also frequently reported (9,19).…”

Insecticied effect of silver and zinc nanoparticles against Aphis nerii Boyer of fonscolombe (Hemiptera: Aphididae)

“…Silver has been used in many applications in pure free metal or in compound form because it possesses antimicrobial activity against pathogens, yet it is nontoxic to humans (Yeo et al, 2003;Elchiguerra et al, 2005). Zinc nanoparticles have antimicrobial activity and can be used as fungicide (Seven et al, 2004;Levin et al, 2007). The authors of these studies have reported that the oxide nanoparticles such as ZnO and Ag have a toxic effect on bacteria, fungi, and biological cells; furthermore, various toxicity mechanisms of Ag have been reported.…”