title: The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients.
abstract: Imatinib mesylate (signal transduction inhibitor 571, Gleevec) is a potent and selective tyrosine kinase inhibitor, which was shown to effectively inhibit platelet-derived growth factor-induced glioblastoma cell growth preclinically. However, in patients, a limited penetration of imatinib into the brain has been reported. Imatinib is transported in vitro and in vivo by P-glycoprotein (P-gp; ABCB1), which thereby limits its distribution into the brain in mice. Previously, imatinib was shown to potently inhibit human breast cancer resistance protein (BCRP; ABCG2). Here, we show that imatinib is efficiently transported by mouse Bcrp1 in transfected Madin-Darby canine kidney strain II (MDCKII) monolayers. Furthermore, we show that the clearance of i.v. imatinib is significantly decreased 1.6-fold in Bcrp1 knockout mice compared with wild-type mice. At t = 2 hours, the brain penetration of i.v. imatinib was significantly 2.5-fold increased in Bcrp1 knockout mice compared with control mice. We tested the hypothesis that P-gp and BCRP inhibitors, such as elacridar and pantoprazole, improve the brain penetration of imatinib. Firstly, we showed in vitro that pantoprazole and elacridar inhibit the Bcrp1-mediated transport of imatinib in MDCKII-Bcrp1 cells. Secondly, we showed that co-administration of pantoprazole or elacridar significantly reduced the clearance of i.v. imatinib in wild-type mice by respectively 1.7-fold and 1.5-fold. Finally, in wild-type mice treated with pantoprazole or elacridar, the brain penetration of i.v. imatinib significantly increased 1.8-fold and 4.2-fold, respectively. Moreover, the brain penetration of p.o. imatinib increased 5.2-fold when pantoprazole was co-administered in wild-type mice. Our results suggest that co-administration of BCRP and P-gp inhibitors may improve delivery of imatinib to malignant gliomas.
authors.affiliation: Division of Experimental Therapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Pauline
authors.initials: P
authors.lastname: Breedveld
authors.forename: Dick
authors.initials: D
authors.lastname: Pluim
authors.forename: Greta
authors.initials: G
authors.lastname: Cipriani
authors.forename: Peter
authors.initials: P
authors.lastname: Wielinga
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; 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; D001549:Benzamides; D001562:Benzimidazoles / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008566:Membranes / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077402:Pantoprazole; D010879:Piperazines / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D018411:Spodoptera; D013454:Sulfoxides / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D001549:Benzamides; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D013454:Sulfoxides; D044005:Tetrahydroisoquinolines; D000068877:Imatinib Mesylate; D000077402:Pantoprazole; D009853:Omeprazole; C083501:Elacridar; D008727:Methotrexate