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Cloning of transporters for anionic drugs and the application to pharmacokinetic analysis

阴离子药物转运蛋白的克隆及其在药代动力学分析中的应用

基本信息

批准号：
11557005
负责人：
KANAI Yoshikatsu
金额：
$ 8.51万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557005/
关键词：
transporter organic anion organic cation drug transport pharmacokinetics blood-brain barrier kidney molecular cloning organic anion transporter drug transporter pharmacokinetics kidney liver brain placenta cloning

项目摘要

The purpose of this study is to identify new members of organic anion transporters of SLC22 family essential for the understanding of the pharmacokinetics of various drugs and xenobiotics. The final goal of this research is to establish the role of organic anion transporters in the pharmacokinetics by revealing the functions and tissue and cellular distribution of the human transporters. In the present study, we have identified six new members of the SLC22 family including OAT4 (organic anion transporter 4), OAT5, OAT6, OAT7, CT2 (carnitine transporter 2) and URAT1 (urate transporter 1). OAT4, OAT5 and OAT7 exhibit similar substrate selectivity preferring sulfate conjugates such as estrone sulgfate. OAT4 and OAT5 are present in the apical membrane of renal proximal tubules of human and rat, respectively. In contrast, OAT7 is present in the sinusoidal membrane of hepatocytes. Therefore, it is proposed that the sulfate conjugates formed in hepatocytes move into blood through OAT7 and taken up by renal proximal tubule epithelial cells via OAT1 and OAT3 on the basolateral membrane and excreted into urine via apical membrane OAT4 or OAT5. URAT1 is present in the apical membrane of renal proximal tubules and functions as an organic anion exchanger transporting urate, lactate, pyradine carboxylate and nicotinate. URAT 1 is responsible for the renal reabsorption of urate. Its genetic defect has turned out to be a cause of idiopathic renal hypouricemia. CT2 and OAT6 are carnitine transporters with different properties. It is notable that CT2 is expressed specifically in testis and is suggested to be important for sperm maturation. In addition, by generating cell lines stably expressing human organic anion transporters and analyzing the properties of the transport of various organic compounds using the cell lines, we have demonstrated that those cells lines are quite useful in the in vitro prediction of drug-drug interactions.

本研究的目的是鉴定 SLC22 家族有机阴离子转运蛋白的新成员，这对于了解各种药物和异生素的药代动力学至关重要。本研究的最终目标是通过揭示人体转运蛋白的功能以及组织和细胞分布来确定有机阴离子转运蛋白在药代动力学中的作用。在本研究中，我们鉴定了SLC22家族的六个新成员，包括OAT4（有机阴离子转运蛋白4）、OAT5、OAT6、OAT7、CT2（肉碱转运蛋白2）和URAT1（尿酸盐转运蛋白1）。 OAT4、OAT5 和 OAT7 表现出相似的底物选择性，更喜欢硫酸酯缀合物，例如硫酸雌酮。 OAT4和OAT5分别存在于人和大鼠肾近曲小管的顶膜中。相反，OAT7 存在于肝细胞的窦膜中。因此，推测肝细胞中形成的硫酸盐结合物通过OAT7进入血液，并通过基底外侧膜上的OAT1和OAT3被肾近曲小管上皮细胞摄取，并通过顶膜OAT4或OAT5排泄到尿液中。 URAT1 存在于肾近曲小管的顶膜中，充当运输尿酸盐、乳酸、吡啶羧酸盐和烟酸盐的有机阴离子交换剂。 URAT 1 负责肾脏对尿酸盐的重吸收。其遗传缺陷已被证明是特发性肾性低尿酸血症的原因。 CT2 和 OAT6 是具有不同特性的肉碱转运蛋白。值得注意的是，CT2 在睾丸中特异性表达，并且被认为对精子成熟很重要。此外，通过生成稳定表达人类有机阴离子转运蛋白的细胞系并使用细胞系分析各种有机化合物的转运特性，我们已经证明这些细胞系在药物-药物相互作用的体外预测中非常有用。