Hepatic and Endocrine Effects of Azole Antifungal Agents

Abstract

The group of drugs known collectively as the azoles, comprising a number of 1-substituted imidazole and triazole compounds, undoubtedly represents the modern approach to both topical and systemic treatment of fungal disease. The first generation of azole antifungals, lipophilic imidazole compounds such as clotrimazole, econazole and miconazole, exhibited poor systemic availability following oral administration, due to both poor absorption and ex-tensive first-pass metabolism. Their use has consequently been essentially limited to topical treatment of superficial fungal infections. Ketoconazole, a more polar imidazole introduced into therapy in the late 1970s (Thienpont et al. 1979), represented a breakthrough in the treatment of antifungal disease since it was the first imidazole agent with good oral bioavailability in humans (Heel et al. 1982). Consequently, it was introduced for the treatment of both superficial and systemic fungal infections by oral administration. The subsequent extensive systemic use of ketoconazole resulted in the appearance of two major classes of side effect: drug-related idiosyncratic hepatitis and decreased plasma concentrations of steroid hormones. In addition, and some-what less serious in impact, the drug has also been shown to interfere with the metabolism of a number of co-administered drugs.