Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices
Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices
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DOI：
10.1124/jpet.107.121491
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发表时间：
2007-09-01
影响因子：
3.5
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Nozaki, Yoshitane;Kusuhara, Hiroyuki;Sugiyama, Yuichi
据报道，同时使用非甾体抗炎药（NSAID）、丙磺舒和其他药物可延迟患者血浆中甲氨蝶呤的消除。以前，我们曾报道，抑制摄取过程不能解释这种药物相互作用，使用大鼠。本研究定量评价了转运蛋白在这种药物相互作用中的可能作用，使用人肾切片和表达人ATP结合盒（ABC）转运蛋白的膜囊泡。人肾切片对甲氨蝶呤的摄取是饱和的，Km为45 - 49 μ M。对氨基马尿酸盐和青霉素可明显抑制人肾切片对甲氨蝶呤的饱和摄取，而5-甲基四氢叶酸的抑制作用较弱。这些转运特征与基底外侧有机阴离子转运蛋白（OAT）3/SLC 22 A8的转运特征相似。NSAID和丙磺舒可抑制人肾脏对甲氨蝶呤的摄取，特别是水杨酸盐、吲哚美辛、保泰松和丙磺舒，预计在临床观察到的血浆浓度下表现出显著的抑制作用。在ABC转运蛋白中，如BCRP/ABCG 2、多药耐药相关蛋白（MRP）2/ABCC 2和MRP 4/ABCC 4，它们是甲氨蝶呤管腔外排的候选者，NSAID对表达MRP 4的膜囊泡对甲氨蝶呤的ATP依赖性摄取的抑制作用最强。预测水杨酸盐和吲哚美辛在临床血浆浓度下抑制MRP 4。双羟萘酸-葡萄糖醛酸苷以浓度依赖性方式显著抑制甲氨蝶呤的MRP 2介导的转运，而萘普生-葡萄糖醛酸苷无影响。肾摄取（通过OAT 3）和外排过程（通过MRP 2和MRP 4）的抑制解释了甲氨蝶呤与丙磺舒和一些NSAID（包括其葡萄糖醛酸苷）的药物相互作用的可能位点。
Simultaneous use of nonsteroidal anti-inflammatory drugs ( NSAIDs), probenecid, and other drugs has been reported to delay the plasma elimination of methotrexate in patients. Previously, we have reported that inhibition of the uptake process cannot explain such drug-drug interactions using rats. The present study quantitatively evaluated the possible role of the transporters in such drug-drug interactions using human kidney slices and membrane vesicles expressing human ATP-binding cassette (ABC) transporters. The uptake of methotrexate by human kidney slices was saturable with a K m of 45 to 49 mu M. Saturable uptake of methotrexate by human kidney slices was markedly inhibited by p-aminohippurate and benzylpenicillin, but only weakly by 5-methyltetrahydrofolate. These transport characteristics are similar to those of a basolateral organic anion transporter (OAT) 3/SLC22A8. NSAIDs and probenecid inhibited the uptake of methotrexate by human kidney and, in particular, salicylate, indomethacin, phenylbutazone, and probenecid were predicted to exhibit significant inhibition at clinically observed plasma concentrations. Among ABC transporters, such as BCRP/ABCG2, multidrug resistance-associated protein (MRP) 2/ABCC2, and MRP4/ABCC4, which are candidates for the luminal efflux of methotrexate, ATP-dependent uptake of methotrexate by MRP4-expressing membrane vesicles was most potently inhibited by NSAIDs. Salicylate and indomethacin were predicted to inhibit MRP4 at clinical plasma concentrations. Diclofenac-glucuronide significantly inhibited MRP2-mediated transport of methotrexate in a concentration-dependent manner, whereas naproxen-glucuronide had no effect. Inhibition of renal uptake (via OAT3) and efflux processes (via MRP2 and MRP4) explains the possible sites of drug-drug interaction for methotrexate with probenecid and some NSAIDs, including their glucuronides.