Open AccessPharmacokinetics of Quinacrine Efflux from Mouse Brain via the P-glycoprotein Efflux Transporter
Author(s) -
Misol Ahn,
Sina Ghaemmaghami,
Yong Huang,
PuayWah Phuan,
Barnaby C. H. May,
Kurt Giles,
Stephen J. DeArmond,
Stanley B. Prusiner
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0039112
Subject(s) - efflux , pharmacokinetics , pharmacology , transporter , p glycoprotein , atp binding cassette transporter , distribution (mathematics) , metabolism , chemistry , biology , biochemistry , multiple drug resistance , gene , antibiotics , mathematical analysis , mathematics
The lipophilic cationic compound quinacrine has been used as an antimalarial drug for over 75 years but its pharmacokinetic profile is limited. Here, we report on the pharmacokinetic properties of quinacrine in mice. Following an oral dose of 40 mg/kg/day for 30 days, quinacrine concentration in the brain of wild-type mice was maintained at a concentration of ∼1 µM. As a substrate of the P-glycoprotein (P-gp) efflux transporter, quinacrine is actively exported from the brain, preventing its accumulation to levels that may show efficacy in some disease models. In the brains of P-gp–deficient Mdr1 0/0 mice, we found quinacrine reached concentrations of ∼80 µM without any signs of acute toxicity. Additionally, we examined the distribution and metabolism of quinacrine in the wild-type and Mdr1 0/0 brains. In wild-type mice, the co-administration of cyclosporin A, a known P-gp inhibitor, resulted in a 6-fold increase in the accumulation of quinacrine in the brain. Our findings argue that the inhibition of the P-gp efflux transporter should improve the poor pharmacokinetic properties of quinacrine in the CNS.