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.

我们研究了基于药物暴露系统在体外重建药物相互作用的新型系统的开发。首先，我们克隆并表征了两个肾脏有机阴离子转运蛋白OAT1和OAT-K2。使用X Enopus卵母细胞表达系统，OAT1介导了各种有机阴离子的摄取，并且在存在各种阴离子利尿剂的情况下，OAT1介导的P-氨基硫酸摄取被显着抑制。另外，燕麦质量介导的疏水有机阴离子的转运（Masuda等，Mol。pharmacol。，55,743-752,1999）。我们已经构建了各种变换剂，稳定地表达了OAT-K1，OAT-K1，OAT-K2，oat-k2，肾脏有机阳离子transporter oct1 and oct2。 OAT-K1介导的方法二邻苯二甲酸的转运受到非甾体类抗炎药的竞争抑制，例如散甲发现和酮酸蛋白和酮酸（Masuda等，J。Pharmacol。Exp。Ther。四烷基铵，抗心血症，内源性代谢物NYI D11E D1-甲基二氨酸胺和鸟根（Urakami等人，J。Pharmaracol。Ther。，287，800-805，1998）。此外，我们证明了克拉霉素对通过P-糖蛋白肾脏排泄的抑制作用（Wakasugi等，Clin。，Ther。，64，123-128，1998）。这些结果表明，药物转运蛋白表达系统似乎对评估和预测转运蛋白介导的药物相互作用有用。