The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins
The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins
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DOI：
10.1002/jps.10395
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发表时间：
2003-06-01
影响因子：
3.8
通讯作者：
Drewe, J
中科院分区：
文献类型：
--
作者：
Bogman, K;Erne-Brand, F;Drewe, J
各种各样的七个非离子，两性和阴离子表面活性剂，应用或研究作为表面活性剂在药物制剂中，进行了分析，他们的能力，调节载体介导的外排泵运输。使用两种细胞系（过表达P-糖蛋白（P-gp）的鼠单核细胞白血病细胞和稳定过表达人多药耐药相关蛋白2（MRP 2）的Madin-Darby犬肾细胞）作为试验系统。通过逆转罗丹明123和甲基荧光素-谷胱甘肽结合物转运分别研究了P-gp和MRP 2功能的调节。与转运蛋白无关并可能导致误解的机制被确定，如探针淬灭、胶束包裹探针和膜损伤。P-gp介导的罗丹明123转运被5种非离子表面活性剂以浓度依赖性方式抑制，其顺序为TPGS > Pluronic PE 8100> Cremophor EL > Pluronic PE 6100，与吐温80接近。相比之下，没有表面活性剂表现出显着抑制MRP 2介导的外排在Madin-Darby犬肾/MRP 2细胞。总之，结果表明，表面活性剂表现出转运蛋白特异性相互作用，而不是非特异性膜透化。本分析提供了深入了解表面活性剂与生物膜相互作用的可能机制，并可能有助于确定特定的药物制剂。(C)2003 Wiley-Liss，Inc.和美国制药协会J Pharm.
A variety of seven nonionic, one amphoteric and, one anionic surfactant that are applied or investigated as surfactants in drug formulation, were analyzed for their capacity to modulate carrier-mediated transport by efflux pumps. Two cell lines, murine monocytic leukemia cells overexpressing P-glycoprotein (P-gp) and Madin-Darby canine kidney cells stably overexpresssing human multidrug resistance-associated protein 2 (MRP2), were used as test systems. The modulation of P-gp and of MRP2 function was studied by the reversal of rhodamine 123 and of methylfluoreseein-glutathione conjugate transport, respectively. Mechanisms that were not transporter related and could lead to misinterpretations were identified, such as probe quenching, probe encapsulation by micelles, and membrane damage. P-gp-mediated rhodamine 123 transport was inhibited by five nonionic surfactants in a concentration-dependent manner and in the order TPGS > Pluronic PE8100 > Cremophor EL > Pluronic PE6100 approximate to Tween 80. In contrast, none of the surfactants showed a significant inhibition of MRP2-mediated efflux in Madin-Darby canine kidney/MRP2 cells. In conclusion, the results indicate that surfactants demonstrate a transporter-specific interaction, rather than unspecific membrane permeabilization. The present analysis offers insight in the possible mechanisms of surfactant interactions with biological membranes and could help to identify specific drug formulations. (C) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm.