Interaction of imatinib mesilate with human P-glycoprotein.

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Hamada A, Miyano H, Watanabe H, Saito H

Interaction of imatinib mesilate with human P-glycoprotein.

J Pharmacol Exp Ther. 2003 Nov;307(2):824-8. Epub 2003 Sep 15.

PubMed ID

12975485 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Imatinib	P-glycoprotein 1	Protein	Humans	No	Substrate Inhibitor	Details