Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state.

Abstract

The objective of this study was to characterize the pharmacokinetic parameters and penetration of fluconazole following a single dose in the serum, aqueous humor, vitreous humor and cerebrospinal fluid (CSF) of non pigmented rabbits using serial sampling techniques and to determine if the pharmacokinetic parameters in the eye and CSF are similar. Twenty healthy male rabbits received intravenous fluconazole 20 mg/kg as a single dose or 20 mg/kg every 12 hours for 4 doses. Serum, aqueous humor, vitreous humor and CSF samples were taken 15 minutes after the initial intravenous injection and hourly thereafter for six hours. Fluconazole concentrations were determined by microbiological assay. Pharmacokinetic analyses were performed using a nonlinear least-square regression program. Fluconazole's penetration in all anatomical compartments was > 70% than in the serum. Similar elimination half-lives and time to reach maximum concentrations were noted in all compartments. While mean concentrations in each anatomical compartment were similar in animals receiving a single dose or among those at serum steady state, the mean concentrations achieved in the serum, aqueous and vitreous humors and CSF were between 1.82 and 2.17 times higher at serum steady state than following a single dose. At serum concentrations that are comparable to those in humans, the penetration of fluconazole into the noninflamed aqueous and vitreous humors and CSF were > or = 70%. The CSF and ocular pharmacokinetic parameters closely resembled each other, so that either could be used as a surrogate for the other.