RT Journal Article
SR Electronic
T1 QUINACRINE IS MAINLY METABOLIZED TO MONO-DESETHYL QUINACRINE BY CYP3A4/5 AND ITS BRAIN ACCUMULATION IS LIMITED BY P-GLYCOPROTEIN
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1136
OP 1144
DO 10.1124/dmd.105.008664
VO 34
IS 7
A1 Yong Huang
A1 Hideaki Okochi
A1 Barnaby C. H. May
A1 Giuseppe Legname
A1 Stanley B. Prusiner
A1 Leslie Z. Benet
A1 B. Joseph Guglielmo
A1 Emil T. Lin
YR 2006
UL http://dmd.aspetjournals.org/content/34/7/1136.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics