title: Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier.
abstract: Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild-type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild-type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1.
authors: Université Paris Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 et Université Paris 7, FranceINSERMS U705, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Novartis Pharma AG, Basel, SwitzerlandAP-HP, Hôpital Fernand Widal, Paris, France.
authors: Sébastien
authors: S
authors: Bihorel
authors: Université Paris Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 et Université Paris 7, FranceINSERMS U705, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Novartis Pharma AG, Basel, SwitzerlandAP-HP, Hôpital Fernand Widal, Paris, France.
authors: Gian
authors: G
authors: Camenisch
authors: Université Paris Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 et Université Paris 7, FranceINSERMS U705, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Novartis Pharma AG, Basel, SwitzerlandAP-HP, Hôpital Fernand Widal, Paris, France.
authors: Michel
authors: M
authors: Lemaire
authors: Université Paris Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 et Université Paris 7, FranceINSERMS U705, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Novartis Pharma AG, Basel, SwitzerlandAP-HP, Hôpital Fernand Widal, Paris, France.
authors: Jean-Michel
authors: JM
authors: Scherrmann
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001549:Benzamides; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000378:metabolism* / Q000493:pharmacokinetics; D011804:Quinolines / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; 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; D000166:Acridines; D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D003524:Cyclosporins; D003986:Dibenzocycloheptenes; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C095179:zosuquidar trihydrochloride; D000068877:Imatinib Mesylate; C095122:multidrug resistance protein 3; C507084:Abcb1b protein, mouse; C083501:Elacridar; C070272:valspodar