Fluconazole distribution to the brain: A crossover study in freely-moving rats using in vivo microdialysis

Purpose. The purpose of this study was to determine if the microdialysis sampling technique is feasible to study the central nervous system distributional kinetics of a novel triazole antifungal agent, fluconazole, in an awake, freely-moving rat model, and to determine fluconazole distribution to the extracellular fluid (ECF) of the brain. Methods. The relative recovery of the microdialysis probes (CMA-12) was determined in vitro and in vivo by retrodialysis using UK54,373, a fluorinated analog of fluconazole. Sprague-Dawley rats received 10 mg/kg and 20 mg/kg fluconazole IV bolus doses in a crossover design, and brain extracellular fluid fluconazole concentrations were monitored using microdialysis and on-line HPLC analysis. The plasma fluconazole concentration vs. time data were determined using sequential blood sampling and HPLC analysis. Results. There was no statistical difference between relative probe recoveries for both fluconazole and UK-54,373, either in vitro or in vivo, and probe recoveries did not change during the course of the in vivo crossover experiment. Fluconazole rapidly distributes into in the brain ECF and the average brain distribution coefficient (brain/plasma AUC ratio) was 0.60 ± 0.18 and was independent of dose. Plasma pharmacokinetic parameters were linear in the dose range studied. Conclusions. Fluconazole rapidly reaches a distributional equilibrium between brain extracellular fluid and plasma, and the distribution to the brain is substantial and;lot dependent on dose over a two-fold range. Furthermore, the results indicate that microdialysis utilizing UK-54,373 as the in vivo retrodialysis probe calibrator is a feasible method to study the transport of fluconazole into the central nervous system.