NR AVDN
AU Huang,Y.; Okochi,H.; May,B.C.H.; Legname,G.; Prusiner,S.B.; Benet,L.Z.; Guglielmo,B.J.; Lin,E.T.
TI Quinacrine is mainly metabolized to mono-desethyl quinacrine by CYP3A4/5 and its brain accumulation is limited by P-glycoprotein
QU Drug Metabolism and Disposition 2006 Jul; 34(7): 1136-44
PT journal article
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]-phen yl)-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.
MH ATP-Binding Cassette Transporters/genetics/*metabolism; Animals; Antimalarials/*pharmacokinetics; Biotransformation; Blood-Brain Barrier/metabolism; Brain/*metabolism; Cell Line; Comparative Study; Cytochrome P-450 Enzyme System/antagonists &; inhibitors/genetics/*metabolism; Dogs; Enzyme Inhibitors/pharmacology; Humans; Ketoconazole/pharmacology; Liver/metabolism; Male; Mice; Mice, Knockout; Microsomes, Liver; P-Glycoproteins/genetics/*metabolism; Quinacrine/*pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins/metabolism; Research Support, N.I.H., Extramural
AD Yong Huang, Hideaki Okochi, Leslie Z. Benet, Emil T. Lin (etlin@itsa.ucsf.edu), Department of Biopharmaceutical Sciences, University of California, San Francisco, California, USA; Barnaby C. H. May, Giuseppe Legname, Stanley B. Prusiner, Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, California, USA; Stanley B. Prusiner, Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA; B. Joseph Guglielmo, Department of Clinical Pharmacy, University of California, CA 94143-0446, San Francisco, California, USA
SP englisch
PO USA