Uric acid analogue as a possible xenobiotic marker of uric acid transporter Urat1 in rats
Uric acid analogue as a possible xenobiotic marker of uric acid transporter Urat1 in rats
复制标题
DOI：
10.1016/j.dmpk.2018.12.003
复制
发表时间：
2019-04-01
影响因子：
2.1
通讯作者：
Tamar, Ikumi
中科院分区：
文献类型：
--
作者：
Arakawa, Hiroshi;Amezawa, Natsumi;Tamar, Ikumi
肾脏中尿酸重吸收转运蛋白URAT 1抑制剂作为治疗高尿酸血症的药物靶点正引起人们的关注。然而，由于尿酸代谢的物种差异，使用实验室动物难以评价URAT 1抑制剂的体内功效。在本研究中，外源性管理尿酸类似物抗尿酸酶的有用性进行了研究，在体内评估rUrat 1在大鼠中的转运活性。四个尿酸类似物的rUrat 1表达非洲爪蟾卵母细胞的摄取显着高于注水卵母细胞。在代谢研究中，这些化合物的消失可以忽略不计，而尿酸显著降低。当给予大鼠奥昔嘌呤醇时，排泄分数（FE）为0.4，表明奥昔嘌呤醇的重吸收。此外，通过联合施用促尿酸排泄剂FYU-981，奥昔嘌呤醇的FE倾向于增加，但无统计学差异，而奥昔嘌呤醇的血浆浓度不受影响。这些结果表明，虽然它不适合作为体内研究中尿酸的探针，但它是一种潜在的尿酸类似物。我们的研究结果可能有助于发现和开发新的针对URAT 1的促尿酸排泄剂。(C)2018年日本异生物学研究学会。由爱思唯尔有限公司出版。保留所有权利。
The inhibitor of uric acid reabsorptive transporter URAT1 in kidney is drawing attention as a drug target for hyperuricemia. However, it is difficult to evaluate efficacy of URAT1 inhibitors in vivo using laboratory animals due to species difference in uric acid metabolism. In the present study, the usefulness of exogenously administering uric acid analogues resistant to uricase was investigated for in vivo evaluation of transport activity of rUrat1 in rats. Uptake of examined four uric acid analogues by rUrat1-expressing Xenopus oocytes was significantly higher than that by water-injected oocytes. In metabolism studies, disappearance of these compounds was negligible, while uric acid was significantly decreased. When oxypurinol was administered to rats, fractional excretion (FE) was 0.4, suggesting reabsorption of oxypurinol. Moreover, FE of oxypurinol was tended to be increased, but not statistically different, by co-administration of a uricosuric agent FYU-981, while plasma concentration of oxypurinol was not affected. These results suggested that oxypurinol is a potential uric acid analogue, although it was not suitable as a probe of uric acid in in vivo study. Our findings may contribute to discovery and development of novel uricosuric agent targeting URAT1. (C) 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.