Interaction of imatinib mesilate with human P-glycoprotein
Interaction of imatinib mesilate with human P-glycoprotein
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DOI：
10.1124/jpet.103.055574
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发表时间：
2003-11-01
影响因子：
3.5
通讯作者：
Saito, H
中科院分区：
文献类型：
--
作者：
Hamada, A;Miyano, H;Saito, H
以猪肾上皮细胞株LLC-PK1和顶膜高表达人P-糖蛋白(P-gp)的L多药耐药细胞为对照，研究了甲磺酸伊马替尼与P-糖蛋白(P-gp)的相互作用。甲磺酸伊马替尼在L多药耐药细胞中从底部到顶端的转运显著高于亲代细胞。甲磺酸伊马替尼作用于LLC-PK1和L-mdr1细胞后，其细胞内蓄积量分别为35%和15%。P-gp调节剂环孢素A可抑制L多药耐药细胞从基底到根尖的转运。经罗丹明123外排试验表明，甲磺酸伊马替尼在高表达人P-gp的K562/DXR细胞中的外排可被甲磺酸伊马替尼显著阻断，且呈剂量依赖关系。用钙调素-AM外排法估算环孢素A和甲磺酸伊马替尼抑制P-gp功能的K-I值分别为6.1和18.3微米。这些观察结果表明，甲磺酸伊马替尼既是人P-gp的底物，也是P-gp的调节剂，提示甲磺酸伊马替尼药物相互作用可能通过P-gp发生。有必要通过P-gp研究甲磺酸伊马替尼与其他药物的药代动力学和药效学相互作用。
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 LLC-PK1 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 K-i 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.