Effect Of Multidrug Resistance-associated Proteins On The Distribution Of Fluconazole In The Brain

Objective:1. To explore the effect of multidrug resistance-associated proteins (MRPs) on the distribution of fluconazole in the brain.2. To compare the difference between the BBB and BCSFB penetration of fluconazole according to physiological condition.3. To estimate the effect of fluconazole dose on the BBB and BCSFB penetration of fluconazole.Methods:1. Sprague-Dawley rats (n=24, male) were randomly divided into 4 groups. Rats in group A (n=6) received an i.v. injection of 10mg/kg fluconazole. Rats in group B (n=6)received lOmg/kg fluconazole and 150mg/kg MRPs inhibitor probenecid. Rats in group C (n=6) received an i.v. injection of 20mg/kg fluconazole. Rats in group D (n=6)received 20mg/kg fluconazole and 150mg/kg probenecid.2. Microdialysis probes were implanted into the rat's striatum and lateral ventricle to collect brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) continuously after the i.v. injection of fluconazole with or without MRPs inhibitor probenecid. The femoral artery and vein were prepared for blood sampling and injecting drugs.3. High-performance liquid chromatography (HPLC) was used to measure the fluconazole concentrations in brain ECF, CSF and blood.4. The BBB and BCSFB penetration of fluconazole were compared between inhibition groups (Group B and D) and control groups (Group A and C) to explore the effect of MRPs on the distribution of fluconazole in the brain.5. The BBB and BCSFB penetration of fluconazole were compared between the two control groups (Group A and C) to deduce the effect of fluconazole dose on the penetration of fluconazole.Results:1. Probenecid significantly increased the BBB penetration of fluconazole but did not increase the BCSFB penetration of fluconazole.2. The BBB and BCSFB penetration of fluconazole did not significantly differ.3. Higher fluconazole dose made higher fluconazole level in brain ECF and CSF, but the BBB and BCSFB penetration of fluconazole were independent of the dose of fluconazole.Conclusion:1. MRPs are involved in the fluconazole resistance at the BBB but not at the BCSFB.2. The CSF concentration of fluconazole can be used to predict the fluconazole level in the brain.3. Increasing fluconazole dose can made higher fluconazole level in brain ECF and CSF,but can not alter its BBB and BCSFB penetration.