Abstract
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.
Highlights
In the search for inhibitors of PrPSc formation, we and others found that phenothiazines and acridines like quinacrine lowered the levels of PrPSc in scrapie-infected neuroblastoma (ScN2a) cells [1,2]
Puzzled by the lack of therapeutic efficacy, we examined the pharmacokinetic properties of quinacrine in mice
Results from another in-vitro study suggested that quinacrine may be a potent compound for treating glioblastomas by inducing autophagic vacuoles leading to tumor cell death [14]
Summary
In the search for inhibitors of PrPSc formation, we and others found that phenothiazines and acridines like quinacrine lowered the levels of PrPSc in scrapie-infected neuroblastoma (ScN2a) cells [1,2] Those findings suggested the possibility that quinacrine might be an effective therapeutic for the uniformly fatal neurodegenerative disorder Creutzfeldt-Jakob disease (CJD) in humans. As a nonselective inhibitor of phospholipase A2, quinacrine has been suggested as a possible therapeutic for neoplasms and heat-induced injury [12,13] Results from another in-vitro study suggested that quinacrine may be a potent compound for treating glioblastomas by inducing autophagic vacuoles leading to tumor cell death [14]. Quinacrine has been reported to stabilize p53, induce the upregulation of downstream pro-apoptotic molecules, and induce p53-dependent tumor cell death [15]
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