HUMAN CARCINOGENIC RISK ASSESSMENT BASED ON HORMONAL EFFECTS IN A CARCINOGENICITY STUDY IN RATS WITH THE ANTIFUNGAL AGENT, FLUCONAZOLE

Fluconazole is an orally active bis-triazole antifungal agent that act s by selective inhibition of lanosterol 14 alpha-demethylase, a key en zyme for maintenance of the fungal cell wall. It is not genotoxic. In a 2 year carcinogenicity study in Sprague-Dawley rats, fluconazole dec reased mammary fibroadenomas in females and adrenal pheochromocytomas in males, and increased hepatic adenomas in males. The pattern of thes e changes is explicable in terms of a hormonal imbalance, corroborated in other studies with fluconazole in rats by changes in the weights o f hormone-sensitive organs and circulating levels of 17 beta-estradiol . The decreases in mammary tumors are probably a consequence of aromat ase inhibition by fluconazole at high dose levels. The tumor effects o bserved in this study are extremely unlikely to be of relevance to hum ans, since the hormone effects observed in this study do not occur in humans treated with therapeutic dose levels of fluconazole. This study illustrates the importance of seeking a mechanistic interpretation of rodent tumor findings, which may then be assessed for its relevance t o the clinical use of a drug. (C) 1994 Wiley-Liss, Inc.