Pharmacokinetics of quinacrine in the treatment of prion disease

Abstract

Background: Prion diseases are caused by the accumulation of an aberrantly folded isoform ofthe prion protein, designated PrPSc. In a cell-based assay, quinacrine inhibits the conversion ofnormal host prion protein (PrPC) to PrPSc at a half-maximal concentration of 300 nM. While thesedata suggest that quinacrine may be beneficial in the treatment of prion disease, its penetration intobrain tissue has not been extensively studied. If quinacrine penetrates brain tissue in concentrationsexceeding that demonstrated for in vitro inhibition of PrPSc, it may be useful in the treatment ofprion disease.Methods: Oral quinacrine at doses of 37.5 mg/kg/D and 75 mg/kg/D was administered to mice for4 consecutive weeks. Plasma and tissue (brain, liver, spleen) samples were taken over 8 weeks: 4weeks with treatment, and 4 weeks after treatment ended.Results: Quinacrine was demonstrated to penetrate rapidly into brain tissue, achievingconcentrations up to 1500 ng/g, which is several-fold greater than that demonstrated to inhibitformation of PrPSc in cell culture. Particularly extensive distribution was observed in spleen(maximum of 100 μg/g) and liver (maximum of 400 μg/g) tissue.Conclusions: The documented extensive brain tissue penetration is encouraging suggestingquinacrine might be useful in the treatment of prion disease. However, further clarification of thedistribution of both intracellular and extracellular unbound quinacrine is needed. The relativeimportance of free quinacrine in these compartments upon the conversion of normal host prionprotein (PrPC) to PrPSc will be critical toward its potential benefit