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Research ArticleArticle

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
Drug Metabolism and Disposition July 2006, 34 (7) 1136-1144; DOI: https://doi.org/10.1124/dmd.105.008664
Yong Huang
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Hideaki Okochi
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Barnaby C. H. May
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Giuseppe Legname
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Stanley B. Prusiner
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Leslie Z. Benet
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B. Joseph Guglielmo
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Emil T. Lin
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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 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.

Footnotes

  • This study and Y.H. are supported in part through National Institutes of Health Grant AG021601.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.008664.

  • ABBREVIATIONS: QA, quinacrine; ACMA, 9-amino-6-chloro-2-methoxyacridine; LC/MS/MS, liquid chromatography-coupled tandem mass spectrometry; CID, collision-induced dissociation; HLM, human liver microsome; RLM, rat liver microsome; P450, cytochrome P450; mAb-CYP3A4/5, monoclonal antibody to human CYP3A4/5; Papp, apparent permeability; BBB, blood-brain barrier; PrPSc, abnormal isoform of the prion protein; MDCK, Madin-Darby canine kidney; MDR1-MDCK, Madin-Darby canine kidney cells tranfected with multidrug resistance protein 1 gene; P-gp, P-glycoprotein; A to B, apical to basolateral; B to A, basolateral to apical; KO, knockout; WT, wild-type; HPLC, high-performance liquid chromatography; MRM, multiple reaction monitoring; amu, atomic mass unit(s).

    • Received November 28, 2005.
    • Accepted March 27, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (7)
Drug Metabolism and Disposition
Vol. 34, Issue 7
1 Jul 2006
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Research ArticleArticle

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
Drug Metabolism and Disposition July 1, 2006, 34 (7) 1136-1144; DOI: https://doi.org/10.1124/dmd.105.008664

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Research ArticleArticle

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
Drug Metabolism and Disposition July 1, 2006, 34 (7) 1136-1144; DOI: https://doi.org/10.1124/dmd.105.008664
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