Development of novel systems for evaluation and prediction of drug inteactions based on the reconstruction of drug excretion systems in vitro.

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We have studied the development of novel systems for evaluation and prediction of drug interactions based on the reconstruction of drug excretion systems in vitro.First, we cloned and characterized two renal organic anion transporters, OAT1 and OAT-K2. Using X enopus oocyte expression system, OAT1 mediated various organic anion uptake, and the OAT1-mediated p-aminohippuric acid uptake was markedly inhibited in the presence of various anionic diuretics. In addition, OAT-K2 mediated transport of hydrophobic organic anions (Masuda et al., Mol. Pharmacol., 55,743-752,1999).Second, We have constructed the various transfectants, stably expressing OAT-K1, OAT-K2, renal organic cation transporter OCT1 and OCT2, respectively. The OAT-K1-mediated methotrexate transport was competitively inhibited by nonsteroidal antiinflammatory drugs such as indomethacin and ketoprofen (Masuda et al., J. Pharmacol. Exp. Ther., 283, 1039-1043, 1997), The OCT1-and OCT2-mediated tetraethylammonium uptake was markedly inhibited by various cationic drugs, such as tetraalkylammoniums, antiarrthythmis, endogenous metabolite NィイD11ィエD1-methylnicotinamide and guanidine (Urakami et al., J. Pharmacol. Exp. Ther., 287, 800-805, 1998). In addition, we demonstrated the inhibitory effect of clarithromycin on renal excretion of digoxin via P-glycoprotein (Wakasugi et al., Clin. Ther., 64, 123-128,1998).These results suggest that the drug transporter expressing systems appeared to be useful for evaluating and predicting the transporter-mediated drug interactions.