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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新系统的发展。首先，我们克隆并鉴定了两个肾脏有机阴离子转运蛋白OAT1和OAT-K2。在X卵母细胞表达系统中，OAT1介导多种有机阴离子摄取，在多种阴离子利尿剂存在下，OAT1介导的对氨基马尿酸摄取被显著抑制。此外，OAT-K2介导的疏水有机阴离子的转运(Masuda et al., Mol. Pharmacol.；, 55743 - 752, 1999)。其次，我们构建了多种转染物，分别稳定表达OAT-K1、OAT-K2、肾有机阳离子转运体OCT1和OCT2。oat - k1介导的甲氨蝶呤转运被非甾体抗炎药如吲哚美辛和酮洛芬竞争性地抑制（Masuda等，J. Pharmacol）。其他实验。各种阳离子药物，如四烷基铵、抗心律失常药、内源性代谢物N - γ -甲基烟酰胺和胍，可显著抑制oct1和oct1介导的四乙基铵摄取（Urakami et al.， J. Pharmacol.）。其他实验。， 287,800 - 805,1998)。此外，我们证明了克拉霉素通过p -糖蛋白抑制地高辛肾排泄的作用(Wakasugi et al.，临床。其他。， 64, 123-128,1998)。这些结果表明，药物转运体表达系统似乎有助于评估和预测转运体介导的药物相互作用。