Pharmacokinetics of quinacrine in the treatment of prion disease.
BACKGROUND
Prion diseases are caused by the accumulation of an aberrantly folded isoform of the prion protein, designated PrPSc. In a cell-based assay, quinacrine inhibits the conversion of normal host prion protein (PrPC) to PrPSc at a half-maximal concentration of 300 nM. While these data suggest that quinacrine may be beneficial in the treatment of prion disease, its penetration into brain tissue has not been extensively studied. If quinacrine penetrates brain tissue in concentrations exceeding that demonstrated for in vitro inhibition of PrPSc, it may be useful in the treatment of prion disease.


METHODS
Oral quinacrine at doses of 37.5 mg/kg/D and 75 mg/kg/D was administered to mice for 4 consecutive weeks. Plasma and tissue (brain, liver, spleen) samples were taken over 8 weeks: 4 weeks with treatment, and 4 weeks after treatment ended.


RESULTS
Quinacrine was demonstrated to penetrate rapidly into brain tissue, achieving concentrations up to 1500 ng/g, which is several-fold greater than that demonstrated to inhibit formation of PrPSc in cell culture. Particularly extensive distribution was observed in spleen (maximum of 100 microg/g) and liver (maximum of 400 microg/g) tissue.


CONCLUSIONS
The documented extensive brain tissue penetration is encouraging suggesting quinacrine might be useful in the treatment of prion disease. However, further clarification of the distribution of both intracellular and extracellular unbound quinacrine is needed. The relative importance of free quinacrine in these compartments upon the conversion of normal host prion protein (PrPC) to PrPSc will be critical toward its potential benefit.
Yung
Lotus
L
Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, California 94143-0622, USA. lotusyung@yahoo.com <lotusyung@yahoo.com>
Huang
Yong
Y
Lessard
Pierre
P
Legname
Giuseppe
G
Lin
Emil T
ET
Baldwin
Michael
M
Prusiner
Stanley B
SB
Ryou
Chongsuk
C
Guglielmo
B Joseph
BJ
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism*; D051379:Mice; D017096:Prion Diseases / Q000188:drug therapy*; D011796:Quinacrine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization; D013154:Spleen / Q000378:metabolism*
D011796:Quinacrine