Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2-and MRP4/ABCC4-mediated methotrexate transport
Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2-and MRP4/ABCC4-mediated methotrexate transport
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DOI：
10.1124/jpet.106.110379
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Russel, Frans G. M.
中科院分区：
文献类型：
--
作者：
El-Sheikh, Azza A. K.;van den Heuvel, Jeroen J. M. W.;Russel, Frans G. M.
甲氨蝶呤(MTX)与非类固醇抗炎药(NSAIDs)联合用于治疗炎症性疾病和恶性肿瘤。尤其是在大剂量的甲氨喋呤时，这种联合用药可能会出现严重的不良反应，通常是由于肾脏排泄受损所致。已经证明，这种相互作用的机制不能完全归因于抑制肾近端小管的基底外侧MTX摄取。在这里，我们研究了不同的非甾体抗炎药对从高表达人多药耐药蛋白(MRP)2/ABCC2和MRP4/ABCC4的细胞中分离的膜泡中MTX转运的影响。甲氨蝶呤由MRP2和MRP4转运，K-m值分别为480+/-90和220+/-70亩M。NSAIDs对MRP4介导的MTX转运的抑制效力一般高于MRP2介导的MTX转运，与治疗相关的IC50值从大约2µM到1.8 mM不等。水杨酸盐、吡罗昔康、布洛芬、萘普生、舒林酸、托美汀和依托度酸根据一位点竞争模型抑制MRP2和MRP4介导的MTX转运。在某些情况下，观察到了更复杂的相互作用模式。双氯芬酸对MRP4的抑制作用和消炎痛和酮洛芬对MRP2的抑制作用遵循双部位竞争模型。苯丁酮在低浓度时刺激MRP2和塞来昔布MRP4的转运，在高浓度时抑制这两种转运蛋白。我们的数据表明，NSAIDs通过MRP2和MRP4抑制肾MTX外流是一个潜在的新的部位和机制，有助于这些药物之间的整体相互作用。
Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs ( NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal elimination. It has been shown that the mechanism of this interaction cannot be fully attributed to inhibition of basolateral MTX uptake in renal proximal tubules. Here, we studied the effect of various NSAIDs on MTX transport in membrane vesicles isolated from cells overexpressing the proximal tubular apical efflux transporters human multidrug resistance protein (MRP) 2/ABCC2 and MRP4/ABCC4. MTX was transported by MRP2 and MRP4 with K-m values of 480 +/- 90 and 220 +/- 70 mu M, respectively. The inhibitory potency of the NSAIDs was generally higher against MRP4- than MRP2-mediated MTX transport, with therapeutically relevant IC50 values, ranging from approximately 2 mu M to 1.8 mM. Salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, and etodolac inhibited MRP2- and MRP4- mediated MTX transport according to a one-site competition model. In some cases, more complex interaction patterns were observed. Inhibition of MRP4 by diclofenac and MRP2 by indomethacin and ketoprofen followed a two-site competition model. Phenylbutazone stimulated MRP2 and celecoxib MRP4 transport at low concentrations and inhibited both transporters at high concentration. Our data suggest that the inhibition by NSAIDs of renal MTX efflux via MRP2 and MRP4 is a potential new site and mechanism contributing to the overall interaction between these drugs.