Ketoconazole Blocks Adrenal Steroid Synthesis

Abstract

Ketoconazole, a broad-spectrum, antifungal drug that is administered orally, inhibits sterol synthesis in fungi. When gynecomastia developed in some patients taking this drug, the effects of ketoconazole on steroid synthesis were investigated in humans and in isolated adrenal cells from rats. In healthy humans, the cortisol response to ACTH was significantly blunted 4 h after a 400 or 600-mg dose. The inhibition persisted for up to 8 h and was absent by 16 h, indicating that adrenal androgen response was reduced. Easily achieved therapeutic concentrations of ketoconazole virtually eliminated corticosterone production by isolated adrenal cells from rats. Although ketoconazole at currently used doses has never been documented to cause clinical hypoadrenalism, caution is urged in high- or multiple-dose trials. The drug may be useful as an agent to block steroid synthesis.