Ocular penetration and pharmacokinetics of topical fluconazole

The high bioavailability and low toxicity of fluconazole, a stable, water-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent. The penetration of fluconazole (0.2%) into the corneas and aqueous humors of New Zealand white rabbits was assayed by gas liquid chromatography (GLC). Peak corneal levels occurred essentially immediately at 5 min in the corneas [debrided, 8.2±1.2 μg/g: nondebrided, 1.6 ± 0.6 μg/g: (mean ± SEM)] and at 15 min after application in the aqueous [debrided, 9.4 ± 2.3 μg/ml: nondebrided. 1.6 ± 0.6 μg/ml: (mean ± SEM)]. Estimating from semilogarithmic plots of the data, the half-life (t( 1/4 )) in the debrided eyes was 15 min: in the nondebrided eyes, t( 1/4 ) was 30 min. A loading dose of a 20-μl drop per min for 5 min yielded levels of 59.9 ± 11.3 μg/g (mean ± SEM) in the debrided corneas and 32.4 ± 1.9 μg/ml (mean ± SEM) in the corresponding aqueous humor. A regimen consisting of this loading dose followed by one 20 μl drop/h for 6 h showed 45.9 ± 3.5 μg/g (mean ± SEM) in the debrided corneas and 8.8 ± 1.7 μg/ml (mean ± SEMI in the corresponding aqueous. The same regimen yielded values of 3.1 ± 0.2 μg/g in the nondebrided corneas and 1.3 ± 0.2 μg/ml (mean ± SEM) in the aqueous. Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from <1.25 to 20 μg/ml, for hyaline molds from 2.5 to >20 μg/ml, and dematiaceous molds from <1.25 to >20 μg/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.