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

Abstract

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.

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

“…Similar to previous reports in mice (Humphrey et al, 1985;Santos et al, 2016) and rats (Uchida et al, 2014;Wang et al, 2017;Yang et al, 1996), we show here that fluconazole rapidly modifies the pharmacokinetic profile of (R,S)-ketamine in mice by increasing total brain exposure of (R,S)-ketamine and (R,S)-norketamine. Concomitantly, fluconazole robustly reduced (2S,6S;2R,6R)-HNK (6-HNK) levels.…”

The role of modeling and simulation to improve the treatment of fungal infections caused by Cryptococcus : A literature review

“…FLZ is a synthetic triazole antifungal used in the treatment of cryptococcal meningoencephalitis and there are countries where it is the only available drug for treating these infections (Sudan et al, 2013;Wang et al, 2017). FLZ is recommended as the main therapeutic agent for the maintenance phase of cryptococcal meningoencephalitis, it has a safety profile, low toxicity, long half-life, physicochemical characteristics that carry on good tissue distribution, is orally bioavailable, has excellent CNS penetration, and has a linear PK (Wang et al, 2017;Santos et al, 2016;Alves et al, 2018;Hope et al, 2019).…”

“…However, the increases in the AUC 0−300 values of the plasma and CSF with probenecid were not significant. Furthermore, probenecid significantly increased the penetration of FLZ into the brain (Wang et al, 2017). Sudan et al, (2013) estimated the PK/PD index of FLZ for cryptococcal meningoencephalitis using a mice infected with clinical isolates of C. neoformans after dosing regimens of 125 and 250 mg/kg once daily for 9 days.…”