Interactions of human organic anion transporters with diuretics
Interactions of human organic anion transporters with diuretics
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DOI：
10.1124/jpet.103.059139
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发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Endou, H
中科院分区：
文献类型：
--
作者：
Hasannejad, H;Takeda, M;Endou, H
近曲小管中利尿剂的肾小管分泌已被证明对于药物的作用至关重要。为了阐明利尿剂肾小管排泄的分子机制，我们使用稳定表达 hOAT 的细胞阐明了人有机阴离子转运蛋白 (hOAT) 与利尿剂的相互作用。测试的利尿剂为噻嗪类，包括氯噻嗪、环噻嗪、氢氯噻嗪和三氯噻嗪；袢利尿剂，包括布美他尼、依他尼酸和呋塞米；和碳酸酐酶抑制剂，包括乙酰唑胺和醋甲唑胺。这些利尿剂以竞争性方式抑制 hOAT1、hOAT2、hOAT3 和 hOAT4 介导的有机阴离子摄取。 hOAT1 对噻嗪类药物表现出最高的亲和力相互作用，而 hOAT3 对袢利尿剂表现出最高的亲和力相互作用。 hOAT1、hOAT3 和 hOAT4（但 hOAT2 除外）介导布美他尼的摄取。 hOAT3 和 hOAT4，但 hOAT1 不介导布美他尼的流出。 hOAT1 和 hOAT3，但 hOAT2 和 hOAT4 不介导呋塞米的摄取。总之，hOAT1可能在噻嗪类药物的基底外侧摄取中发挥重要作用，hOAT3可能在袢利尿剂的摄取中发挥重要作用。另外，还提出被hOAT3和/或hOAT1摄取的布美他尼被hOAT4排泄到尿液中。
The tubular secretion of diuretics in the proximal tubule has been shown to be critical for the action of drugs. To elucidate the molecular mechanisms for the tubular excretion of diuretics, we have elucidated the interactions of human organic anion transporters (hOATs) with diuretics using cells stably expressing hOATs. Diuretics tested were thiazides, including chlorothiazide, cyclothiazide, hydrochlorothiazide, and trichlormethiazide; loop diuretics, including bumetanide, ethacrynic acid, and furosemide; and carbonic anhydrase inhibitors, including acetazolamide and methazolamide. These diuretics inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4 in a competitive manner. hOAT1 exhibited the highest affinity interactions for thiazides, whereas hOAT3 did those for loop diuretics. hOAT1, hOAT3, and hOAT4 but not hOAT2, mediated the uptake of bumetanide. hOAT3 and hOAT4, but not hOAT1 mediated the efflux of bumetanide. hOAT1 and hOAT3, but not hOAT2 and hOAT4 mediated the uptake of furosemide. In conclusion, it was suggested that hOAT1 may play an important role in the basolateral uptake of thiazides, and hOAT3 in the uptake of loop diuretics. In addition, it was also suggested that bumetanide taken up by hOAT3 and/or hOAT1 is excreted into the urine by hOAT4.