Elucidation of the transporters, and integration research of their molecular entities and activities for the drug transport in the brain and kidneys

转运蛋白的阐明，及其分子实体和大脑和肾脏药物转运活性的整合研究

• 批准号: 23390034
• 负责人: KUSUHARA Hiroyuki
• 金额: $ 11.73万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23390034/
• 关键词: 薬物動態; SLCトランスポーター; 腎排泄; 薬物間相互作用; 血液脳関門; 中枢移行性; 薬物トランスポーター; 腎尿細管分泌; 内因性基質; 再吸収

This study elucidated that MATEs which act as H+/organic cation exchanges mediate the urinary excretion of various drugs, endogenous metabolite (N-methylnicotinamide) and fluorescents in mouse, and that inhibition of MATEs is part of the mechanism underlying the drug-drug interactions in the urinary excretion with cimetidine and trimethoprim. NPT4 mediates facilitated diffusion of various anionic drugs such as diuretics in HEK293 cells. MCT9 is found to be expressed on the basolateral membrane of the proximal tubules. Among the drugs which undergo urinary excretion, OCT2 can recognize only hydrophilic compounds as substrate. MCT9 also acts as organic cation transporter showing substrate specificity distinct from OCT2. Since MCT9 is also expressed in the blood-brain barrier, it is speculated that MCT9 is involved in the disposition of drugs in the central nervous system in addition to the kidney.

This study elucidated that MATEs which act as H+/organic cation exchanges mediate the urinary excretion of various drugs, endogenous metabolite (N-methylnicotinamide) and fluorescents in mouse, and that inhibition of MATEs is part of the mechanism underlying the drug-drug interactions in the urinary excretion with cimetidine and trimethoprim. NPT4介导了HEK293细胞中各种阴离子药物（例如利尿剂）的促进。发现MCT9在近端小管的基底外侧膜上表达。在经历尿液排泄的药物中，OCT2只能将亲水性化合物识别为底物。 MCT9还充当有机阳离子转运蛋白，显示出与OCT2不同的底物特异性。由于MCT9在血脑屏障中也表达，因此据推测MCT9除了肾脏外，还参与了中枢神经系统中药物的处置。

项目成果

Drug-transport interactions : kinetic concepts and clinical studies to demonstrate relevance of in vitro mode predictions

药物转运相互作用：动力学概念和临床研究以证明体外模式预测的相关性

• 发表时间: 2012
• 作者: Tsuchiya H;Matsunaga T;Aikawa K;Kamada N;Nakamura K;Ichikawa H;Sasaki K;Ohmori S;Y. Ogra;Otaka A;楠原洋之
• 通讯作者: 楠原洋之

Functional Characterization of organic cation transport in HEK293 cells

HEK293 细胞中有机阳离子运输的功能表征

• 发表时间: 2012
• 作者: 小林和正;他
• 通讯作者: 他

Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a

使用脑脊液浓度作为定量评估血脑屏障处 p-糖蛋白和乳腺癌抗性蛋白的主动流出对大脑中未结合药物浓度的可预测性的影响

• 发表时间: 2011
• 期刊: J Pharmacol Exp Ther
• 影响因子: 3.5
• 作者: Kodaira H;Kusuhara H;Fujita T;Ushiki J;Fuse E;Sugiyama Y
• 通讯作者: Sugiyama Y

カチオン性医薬品腎排泄過程における薬物間相互作用におけるMATEの関与

MATE参与阳离子药物肾脏排泄过程中的药物相互作用

• 发表时间: 2012
• 作者: R. Sato;B. Felder;M. Miki;K. Tsuzuki;H. Hayakawa;M. Izumi;伊藤澄人
• 通讯作者: 伊藤澄人

Quantitative Investigation of Drug Transport across the BBB

跨 BBB 药物转运的定量研究

• 发表时间: 2012
• 作者: Anan Y;Ogra Y;楠原洋之
• 通讯作者: 楠原洋之