title: Interaction of imatinib mesilate with human P-glycoprotein.
abstract: The interaction of imatinib mesilate with P-glycoprotein (P-gp) was examined using pig kidney epithelial LLC-PK1 cells versus L-MDR1 cells, which overexpress human P-gp on the apical membrane. The basal-to-apical transport of imatinib mesilate in L-MDR1 cells significantly exceeded that in the parental LLCPK1 cells. The intracellular accumulation of imatinib mesilate after its basal application to LLC-PK1 and L-MDR1 cells was 35% and 15%, respectively. A P-gp modulator, cyclosporin A, inhibited the basal-to-apical transport in L-MDR1 cells. The intracellular accumulation of imatinib mesilate in L-MDR1 cells was also increased by cyclosporin A. The rhodamine 123 efflux assay showed that the efflux of rhodamine 123 in K562/DXR cells, which overexpress human P-gp, could be blocked markedly by imatinib mesilate in a dose-dependent fashion. The Ki values for the inhibition of P-gp function by cyclosporin A and imatinib mesilate were estimated to be 6.1 and 18.3 muM, respectively, using a calcein-AM efflux assay. These observations demonstrate that imatinib mesilate is a substrate as well as a modulator of human P-gp, suggesting that imatinib mesilate drug interactions may occur via P-gp. It is necessary to consider the pharmacokinetic and pharmacodynamic interactions of imatinib mesilate with other drugs via P-gp.
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Hideto
authors.initials: H
authors.lastname: Miyano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004347:Drug Interactions; D005452:Fluoresceins / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D005452:Fluoresceins; D005456:Fluorescent Dyes; D010879:Piperazines; D011743:Pyrimidines; C085925:calcein AM; D020112:Rhodamine 123; D000068877:Imatinib Mesylate