Effect of Efflux Transporter Inhibition on the Distribution of Fluconazole in the Rat Brain

Neurochem Res. 2017 Aug;42(8):2274-2281. doi: 10.1007/s11064-017-2240-x. Epub 2017 Mar 24.


Multidrug resistance-associated proteins (MRPs) and organic anion transporters (OATs) are expressed on the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), preventing the entry of or the pumping out of numerous molecules. Fluconazole is widely used to treat fungal meningoencephalitis. The effect of these transporters on the distribution of fluconazole in the brain is unclear. We used microdialysis to compare the distribution of fluconazole in the rat brain with and without co-administration of probenecid, a MRP and OAT inhibitor. Additionally, we also observed the difference in fluconazole distribution between the two barriers. The results showed that probenecid increased the penetration of fluconazole into the BBB but did not alter the penetration of fluconazole into the BCSFB of rats. The penetration of the BBB and BCSFB by fluconazole did not statistically differ according to physiological condition. These results demonstrate that transporters that can be inhibited by probenecid may be involved in fluconazole resistance at the BBB and provide a laboratory basis for predicting brain extracellular fluid (ECF) concentration using the cerebrospinal fluid (CSF) concentration of fluconazole.

Keywords: Blood-brain barrier (BBB); Blood-cerebrospinal fluid barrier (BCSFB); Fluconazole; Multidrug resistance-associated proteins (MRPs); Organic anion transporters (OATs); Probenecid.

MeSH terms

  • Animals
  • Antifungal Agents / metabolism*
  • Antifungal Agents / pharmacology
  • Biological Transport / drug effects
  • Biological Transport / physiology
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain / drug effects
  • Brain / metabolism*
  • Dose-Response Relationship, Drug
  • Fluconazole / metabolism*
  • Fluconazole / pharmacology
  • Male
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Organic Anion Transporters / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution / drug effects
  • Tissue Distribution / physiology


  • Antifungal Agents
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • Fluconazole