title: Cerebrospinal fluid can be used as a surrogate to assess brain exposures of breast cancer resistance protein and P-glycoprotein substrates.
abstract: The objectives of the study were to characterize the selectivity of dantrolene to breast cancer resistance protein (Bcrp) and to evaluate whether cerebrospinal fluid (CSF) can be used as a surrogate to assess brain exposures of BCRP and P-glycoprotein (Pgp) substrates. The impact of Bcrp and Pgp on dantrolene exposures in brain and CSF was examined in Bcrp and Mdr1a/1b knockout mice and was further investigated in wild-type mice in the presence of the Bcrp inhibitor (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester (Ko143), the Pgp inhibitor 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporine A (PSC833), and the dual inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). The effect of Bcrp and Pgp on digoxin exposures in brain and CSF was investigated in wild-type mice in the presence of the inhibitors. In vivo studies showed dantrolene exposures in brain and CSF, but not the blood, increased in Bcrp(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice, or in the presence of the Bcrp inhibitors Ko143 or GF120918. Inhibition of Pgp by GF120918 and PSC833 significantly increased digoxin exposures in brain, CSF, and blood to a lesser extent. Results from the present study demonstrated that inhibition of Bcrp and Pgp increased not only the exposures of dantrolene and digoxin in brain, but also the exposures in CSF. In addition, the change of exposures in CSF reflected the changes in brain. The present study strongly suggests that the dantrolene and digoxin exposures in CSF are primarily determined by the rapid transport from brain to CSF, and inhibition of Bcrp and Pgp exhibits little impact on using CSF as surrogates to assess brain exposures of Bcrp and Pgp substrates.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. guangqing.xiao@biogenidec.com
authors.forename: Guangqing
authors.initials: G
authors.lastname: Xiao
authors.forename: Cheryl
authors.initials: C
authors.lastname: Black
authors.forename: Gregg
authors.initials: G
authors.lastname: Hetu
authors.forename: Eric
authors.initials: E
authors.lastname: Sands
authors.forename: Joy
authors.initials: J
authors.lastname: Wang
authors.forename: Robin
authors.initials: R
authors.lastname: Caputo
authors.forename: Ellen
authors.initials: E
authors.lastname: Rohde
authors.forename: Liang-Shang L
authors.initials: LS
authors.lastname: Gan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D018938:Caco-2 Cells; D003620:Dantrolene / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D004364:Pharmaceutical Preparations; D004077:Digoxin; D003620:Dantrolene