Safety aspects of oral antifungal agents.
Four main targets have to be considered when evaluating the safety of new systemically acting, oral antifungals: the liver, the endocrine system, serum cholesterol and the developing embryo. The major endocrine targets for high levels of the antifungal azoles are the adrenal cortex and the gonads. Endocrine studies demonstrate that itraconazole has little potential for interfering with steroid hormones in man. Available data also indicate that itraconazole has low predictable hepatotoxicity potential in man. In rats, serum cholesterol levels are raised during treatment with itraconazole, especially after chronic exposure. This is, however, a species-specific phenomenon which leads to secondary events at toxic doses, especially in long-term toxicity studies. In man, including patients with existing hypercholesterolaemia, serum cholesterol levels are not raised. Ketoconazole has been shown to be teratogenic at high, toxic doses in pregnant rats. The same observation has been made for itraconazole, and it may also be true for fluconazole. However, all three azoles show no teratogenicity in the rabbit. Studies with itraconazole in adrenalectomised rats and in rats given exogenous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are important mediators of teratogenicity. Since itraconazole does not affect adrenal function at levels used to treat infections in man, the teratogenic risk is estimated to be low. Itraconazole is therefore a promising new drug, especially with regard to the assessment of its safety in the liver and endocrine system. Moreover, it is more potent and has a broader antifungal spectrum than other azole antifungals, and its development is considered to be an important step forward in chemotherapy.
Van Cauteren
H
H
Department of Toxicology, Janssen Research Foundation, Beerse, Belgium.
Lampo
A
A
Vandenberghe
J
J
Vanparys
P
P
Coussement
W
W
De Coster
R
R
Marsboom
R
R
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004702:Endocrine Glands / Q000187:drug effects; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D017964:Itraconazole; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008099:Liver / Q000187:drug effects
D000935:Antifungal Agents; D017964:Itraconazole; D007654:Ketoconazole