title: ABC transporters and the accumulation of imatinib and its active metabolite CGP74588 in rat C6 glioma cells.
abstract: Imatinib (Glivec, Gleevec, STI571) is a small tyrosine kinase inhibitor that is currently in phase II clinical trials in patients with recurrent glioblastoma. Its therapeutic benefit is minimal, although it is greater in some patients when combined with hydroxyurea. Imatinib is transported by human and rodent ATP-binding cassette (ABC) transporters like P-glycoprotein (Pgp) and the breast cancer resistance protein (BCRP). We have investigated whether ABC transporters determine the pharmacokinetics of imatinib and its pharmacological active metabolite CGP74588 in rat C6 glioma cells. ABC transporter expressions were measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). C6 cells express high concentrations of the Pgp-encoding gene Mdr1b and a 10-fold smaller amount of the Pgp-encoding gene Mdr1a. The relative expression of ABC transporter genes are: Mdr1b>Mrp4>Mrp1>Mrp5>Mdr1a>Mrp3>Mrp2>Bcrp. The accumulation of imatinib into C6 cells increased linearly with the extracellular concentration of imatinib (0.5-50microM) and was not increased by zosuquidar (selective Pgp inhibitor) or elacridar (inhibitor of both Pgp and Bcrp). In contrast, there was less CGP74588 than imatinib in C6 cells and its concentration increased with the extracellular concentration in a sigmoid fashion. Lastly, 10microM valspodar (selective Pgp inhibitor), elacridar and zosuquidar all increased the accumulation of CGP74588 by 2.5-fold. Thus CGP74588 is readily transported by the Pgp in rat C6 gliomas cells, which raises the question of the role of Pgp in the resistance of recurrent glioblastomas to imatinib.
authors.affiliation: Université Paris Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 et Université Paris 7, Paris F-75010, France. xavier.decleves@univ-paris5.fr
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bihorel
authors.forename: Marcel
authors.initials: M
authors.lastname: Debray
authors.forename: Salah
authors.initials: S
authors.lastname: Yousif
authors.forename: Gian
authors.initials: G
authors.lastname: Camenisch
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D019540:Area Under Curve; D001549:Benzamides; D001667:Binding, Competitive / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR; D005910:Glioma / Q000378:metabolism*; D000068877:Imatinib Mesylate; D010641:Phenotype; D010879:Piperazines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate