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Drug Metabolism and Disposition Fast Forward
First published on March 31, 2006; DOI: 10.1124/dmd.105.008664

0090-9556/06/3407-1136-1144$20.00
DMD 34:1136-1144, 2006

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QUINACRINE IS MAINLY METABOLIZED TO MONO-DESETHYL QUINACRINE BY CYP3A4/5 AND ITS BRAIN ACCUMULATION IS LIMITED BY P-GLYCOPROTEIN

Yong Huang, Hideaki Okochi, Barnaby C. H. May, Giuseppe Legname, Stanley B. Prusiner, Leslie Z. Benet, B. Joseph Guglielmo, and Emil T. Lin

Department of Biopharmaceutical Sciences (Y.H., H.O., L.Z.B., E.T.L.), Institute for Neurodegenerative Diseases and Department of Neurology (B.C.H.M., G.L., S.B.P.), Department of Biochemistry and Biophysics (S.B.P), and Department of Clinical Pharmacy (B.J.G.), University of California, San Francisco, California

Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human cytochrome (P450) isoforms involved in QA mono-desethylation were identified as CYP3A4/5 by using specific chemical and antibody inhibition as well as cDNA-expressed P450 studies. QA transport from the basolateral to apical side in multidrug resistance protein 1 gene (MDR1)-transfected Madin-Darby canine kidney (MDCK) cells was markedly greater than in control MDCK cells and was inhibited by the potent P-glycoprotein (P-gp) inhibitor GG918 (N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-iso-1-quinolynyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). In MDR1-knockout (KO) mice, QA brain levels were 6 to 9 times higher after a single i.v. dose of 2 mg/kg QA and 49 times higher after multiple oral doses of 10 mg/kg/day QA for 7 days, compared with those in wild-type (WT) FVB mice. In contrast, the QA levels in plasma, liver, spleen, and kidney were similar after a single 2 mg/kg i.v. dose and <2 times greater after 10 mg/kg oral doses in MDR1-KO mice compared with WT mice. These results indicate that P-gp plays a critical role in transporting QA from the brain.

Address correspondence to: Dr. Emil T. Lin, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California San Francisco, San Francisco, CA 94143-0446. E-mail: etlin{at}itsa.ucsf.edu




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P. Spilman, P. Lessard, M. Sattavat, C. Bush, T. Tousseyn, E. J. Huang, K. Giles, T. Golde, P. Das, A. Fauq, et al.
A {gamma}-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains
PNAS, July 29, 2008; 105(30): 10595 - 10600.
[Abstract] [Full Text] [PDF]


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