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

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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.