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

基于体外药物排泄系统重建的药物相互作用评估和预测的新系统的开发。

基本信息

批准号：
09557211
负责人：
INUI Ken-ichi
金额：
$ 8.32万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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.

我们研究了基于体外药物排泄系统重建的药物相互作用评价和预测的新系统的开发。首先，我们利用X enopus卵母细胞表达系统克隆并表征了两种肾脏有机阴离子转运蛋白OAT1和OAT-K2。，OAT1介导的各种有机阴离子的摄取，并且在各种阴离子利尿剂存在下，OAT1介导的对氨基马尿酸的摄取被显着抑制。另外，OAT-K2。介导的疏水性有机阴离子转运（Masuda et al., Mol. Pharmacol., 55,743-752,1999）。其次，我们构建了各种转染子，稳定表达 OAT-K1、OAT-K2、肾有机阳离子转运蛋白 OCT1 和 OCT2 OAT-K1 介导的甲氨蝶呤转运分别被非甾体类抗炎药竞争性抑制。吲哚美辛和酮洛芬 (Masuda et al., J. Pharmacol. Exp. Ther., 283, 1039-1043, 1997)，OCT1 和 OCT2 介导的四乙铵摄取被各种阳离子药物显着抑制，例如四烷基铵、抗心律失常、内源性代谢物N-甲基烟酰胺和胍（Urakami et al., J. Pharmacol. Exp. Ther., 287, 800-805, 1998）此外，我们证明了克拉霉素通过 P-糖蛋白（Wakasugi）对地高辛肾排泄的抑制作用。等人，临床医生，64， 123-128, 1998）。这些结果表明药物转运蛋白表达系统似乎可用于评估和预测转运蛋白介导的药物相互作用。