OCULAR PENETRATION AND PHARMACOKINETICS OF TOPICAL FLUCONAZOLE

The high bioavailability and low toxicity of fluconazole, a stable, wa ter-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent. The penetr ation 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 mu g/g; nondebrided, 1.6 +/- 0.6 mu g/g ; (mean +/- SEM)] and at 15 min after application in the aqueous [debr ided, 9.4 +/- 2.3 mu g/ml; nondebrided, 1.6 +/- 0.6 mu g/ml; (mean +/- SEM)]. Estimating from semilogarithmic plots of the data, the half-li fe (t(1/2)) in the debrided eyes was 15 min; in the nondebrided eyes, t(1/2) was 30 min. A loading dose of a 20-mu l drop per min for 5 min yielded levels of 59.9 +/- 11.3 mu g/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 mu g/ml ml (mean +/- SEM) in the correspondin g aqueous humor. A regimen consisting of this loading dose followed by one 20 mu l drop/h for 6 h showed 45.9 +/- 3.5 mu g/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 mu/ml (mean +/- SEM) in the co rresponding aqueous. The same regimen yielded values of 3.1 +/- 0.2 mu g/g in the nondebrided corneas and 1.3 +/- 0.2 mu g/ml (mean +/- SEM) in the aqueous. Minimal inhibitory concentrations (MIG) at 24 h for y easts ranged from <1.25 to 20 mu g/ml, for hyaline molds from 2.5 to > 20 mu g/ml, and dematiaceous molds from <1.25 to >20 mu g/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit fu rther evaluation for its ophthalmic use as a topical antifungal agent.