Human carcinogenic risk assessment based on hormonal effects in a carcinogenicity study in rats with the antifungal agent, fluconazole

Abstract

Fluconazole is an orally active bis-triazole antifungal agent that acts by selective inhibition of lanosterol 14 alpha-demethylase, a key enzyme for maintenance of the fungal cell wall. It is not genotoxic. In a 2 year carcinogenicity study in Sprague-Dawley rats, fluconazole decreased mammary fibroadenomas in females and adrenal pheochromocytomas in males, and increased hepatic adenomas in males. The pattern of these changes is explicable in terms of a hormonal imbalance, corroborated in other studies with fluconazole in rats by changes in the weights of hormone-sensitive organs and circulating levels of 17 beta-estradiol. The decreases in mammary tumors are probably a consequence of aromatase inhibition by fluconazole at high dose levels. The tumor effects observed in this study are extremely unlikely to be of relevance to humans, 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 to the clinical use of a drug.

In silico environmental risk assessment of fate and effects of pharmaceuticals and their TPs generated and treated by coupling tertiary processes in hospital wastewater

“…Although studies indicate that FCZ can cause tumors, this is extremely unlikely to occur in humans. 75 In recent work, Tamura et al 76 investigated liver hypertrophy and tumor development in mice induced by FCZ and two other triazoles. It was found that FCZ could induce hepatic hypertrophy and the development of tumors in the liver.…”

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“…It was introduced in early 1990 as prophylactic antifungal after bone marrow transplantation 2 . Fluconazole acts by selective inhibition of lanosterol 14-alphademethylase, a key enzyme for maintenance of the fungal cell wall 3 . It has a favourable pharmacokinetic profile that includes a long serum half-lifetime, which makes once-daily administration possible, more consistent absorption from the gastrointestinal tract than that of ketoconazole, excellent penetration into the cerebrospinal fluid, and elimination predominantly by a renal mechanism 4 .…”