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

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Received for publication November 29, 2005.
Revised March 24, 2006.
Accepted for publication March 27, 2006.

Quinacrine Is Mainly Metabolized to Mono-Desethyl Quinacrine by CYP3A4/5 and Its Brain Accumulation Is Limited by P-glycoprotein

Yong Huang 1, Hideaki Okochi 2, Barnaby C.H. May 2, Giuseppe Legname 2, Stanley B. Prusiner 2, Leslie Z. Benet 2, B. Joseph Guglielmo 2, Emil T. Lin 2*

1 University of California,San Francisco 2 UCSF

* Address correspondence to: E-mail: etlin{at}itsa.ucsf.edu

Abstract

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 LC/MS/MS the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human 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 MDR1 transfected MDCK cells was markedly greater than in control MDCK cells and was inhibited by the potent P-gp inhibitor GG918. In MDR1-knockout (KO) mice, QA brain levels were 6-9 times higher after a single intravenous (iv) dose of 2 mg/kg QA and 49 times higher after multiple oral doses of 10 mg/kg/day QA for 7 days, compared to 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 iv and <2 times greater after 10 mg/kg oral doses in MDR1-KO mice compared to WT mice. These results indicate that P-gp plays a critical role in transporting QA from the brain.


Key words: analytical chemistry, blood-brain barrier, CYP3A, cytochrome P450, HPLC, human CYP enzymes, mass spectrometry, metabolite identification, microsomes, p-glycoprotein


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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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