Pharmacokinetics of oral antifungals and their clinical implications

Orally active antifungals have different physicochemical and pharmacokinetic properties. Itraconazole is a broad-spectrum triazole antifungal with pronounced lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic bistriazole antifungal, fluconazole. The pharmacokinetics of itraconazole in man are characterised by good oral absorption (when taken with a meal), an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day, and biotransformation into a large number of metabolites. Distribution studies have shown that therapeutically active levels of intraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for four weeks in the stratum corneum of the skin after treatment has been stopped. These unique distribution characteristics may explain why itraconazole with relatively low plasma concentrations (but with high tissue concentrations) is as effective as fluconazole. Fluconazole interacts with cytochrome P450-dependent enzyme activities in hepatic microsomes of rats and mice. These effects in rodents are seen at plasma and liver concentrations of fluconazole comparable to those obtained in man at therapeutic dose levels. Unlike fluconazole, itraconazole does not interfere with mammalian drug-metabolising enzymes, minimising the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections.