title: Ocular penetration and pharmacokinetics of topical fluconazole.
abstract: 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 micrograms/g; nondebrided, 1.6 +/- 0.6 microgram/g; (mean +/- SEM)] and at 15 min after application in the aqueous [debrided, 9.4 +/- 2.3 micrograms/ml; nondebrided, 1.6 +/- 0.6 microgram/ml; (mean +/- SEM)]. Estimating from semilogarithmic plots of the data, the halflife (t1/2) in the debrided eyes was 15 min; in the nondebrided eyes, t1/2 was 30 min. A loading dose of a 20-microliter drop per min for 5 min yielded levels of 59.9 +/- 11.3 micrograms/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 micrograms/ ml (mean +/- SEM) in the corresponding aqueous humor. A regimen consisting of this loading dose followed by one 20 microliters drop/h for 6 h showed 45.9 +/- 3.5 micrograms/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 micrograms/ml (mean +/- SEM) in the corresponding aqueous. The same regimen yielded values of 3.1 +/- 0.2 micrograms/g in the nondebrided corneas and 1.3 +/- 0.2 micrograms/ml (mean +/- SEM) in the aqueous. Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from < 1.25 to 20 micrograms/ml, for hyaline molds from 2.5 to > 20 micrograms/ml, and dematiaceous molds from < 1.25 to > 20 micrograms/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.
authors.affiliation: Department of Ophthalmology and Visual Science, University of Texas Health Science Center, San Antonio, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Yee
authors.forename: C J
authors.initials: CJ
authors.lastname: Cheng
authors.forename: S
authors.initials: S
authors.lastname: Meenakshi
authors.forename: T M
authors.initials: TM
authors.lastname: Ludden
authors.forename: J E
authors.initials: JE
authors.lastname: Wallace
authors.forename: M G
authors.initials: MG
authors.lastname: Rinaldi
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001082:Aqueous Humor / Q000378:metabolism*; D001682:Biological Availability; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000378:metabolism*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D009883:Ophthalmic Solutions; D011817:Rabbits
chemical_list: D000935:Antifungal Agents; D009883:Ophthalmic Solutions; D015725:Fluconazole