Molecular basis for quantitative prediction of drug-drug interaction at excretion process

排泄过程中药物相互作用定量预测的分子基础

• 批准号: 16590108
• 负责人: KATO Yukio
• 金额: $ 2.3万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590108/
• 关键词: Drug-drug interaction; Transporter; Drug disposition; Membrane transport; Pharmacokinetics; Renal tubular secretion; Kidney; Renal excretion

Recent progress in molecular biology has revealed predominant roles of many types of xenobiotic transporters in drug secretion into the urine and bile, leading to possible occurrence of drug-drug interaction at the excretion processes. Therefore, it is expected to predict the interaction based on in vitro experimental system. This study aimed to clarify molecular basis for the prediction of drug-drug interaction at the excretion process in liver and kidney. As model drugs that are excreted into the bile and urine, a novel uric acid generation inhibitor Y-700 and a novel diuretic M17055 were used. We have suggested involvement of Na^+-dependent organic anion transport system, other than OATP family, in hepatic uptake of Y-700, part of Y-700 uptake being mediated by bile acid transporter NTCP. We have also clarified important role of OAT1 in renal uptake of M17055. Furthermore, we have identified direct interaction of certain types of transporters, that are expressed on apical membranes in kidney and/or small intestine, with PDZ domain containing proteins PDZK family, implying that such protein-protein interaction may play a role in apical localization of the transporters. Among the PDZ proteins, PDZK1 is colocalized on apical membranes in kidney and small intestine with OCTN2, and can stimulate transport activity of several transporters including OCTN1, OCTN2 and PEPT2. Finally, we have focused on functional modulation of oligopeptide transporter PEPT1 by Na^+/H^+ exchanger (NHE) 3 that can also bind to the PDZ proteins and supply H^+ gradient that can be utilized by PEPT1 for transport activity. NHE3 affects transport activity, Na^+- and H^+- dependence of PEPT1. Thus, this study has proposed a novel concept that adaptor proteins (such as PDZK1) and other membrane proteins (such as NHE3), both having interaction potential with transporters, could be important molecular basis for prediction of drug-drug interaction at excretion processes.

近年来分子生物学的研究表明，多种外源性物质转运蛋白在药物分泌到尿液和胆汁中的过程中发挥着重要作用，从而导致药物在排泄过程中可能发生相互作用。因此，有望在体外实验系统的基础上预测相互作用。本研究旨在阐明预测药物在肝、肾排泄过程中相互作用的分子基础。作为排泄到胆汁和尿液中的模型药物，使用了新型尿酸生成抑制剂Y-700和新型利尿剂M17055。我们认为，Y-700的肝摄取可能与OATP家族以外的Na^+依赖性有机阴离子转运系统有关，其中一部分Y-700的肝摄取是由胆汁酸转运蛋白NTCP介导的。我们还阐明了OAT 1在肾脏摄取M17055中的重要作用。此外，我们已经鉴定了在肾脏和/或小肠中的顶膜上表达的某些类型的转运蛋白与含有PDZ结构域的蛋白PDZK家族的直接相互作用，这意味着这种蛋白质-蛋白质相互作用可能在转运蛋白的顶定位中起作用。在PDZ蛋白中，PDZK 1与OCTN 2共定位于肾脏和小肠的顶膜上，并且可以刺激包括OCTN 1、OCTN 2和PEPT 2在内的多种转运蛋白的转运活性。最后，我们重点研究了Na^+/H^+交换剂（NHE）3对寡肽转运蛋白PEPT 1的功能调节，NHE 3也可以与PDZ蛋白结合，并提供PEPT 1可以利用的H^+梯度来进行转运活性。NHE 3影响PEPT 1的转运活性、Na^+和H^+依赖性。因此，本研究提出了一个新的概念，衔接蛋白（如PDZK 1）和其他膜蛋白（如NHE 3），都具有与转运蛋白的相互作用潜力，可能是重要的分子基础，预测药物相互作用的排泄过程。

项目成果

Contribution of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethasone.

在用或不用地塞米松治疗的小鼠中，肠道 P-糖蛋白和 CYP3A 对环孢菌素 A 口服生物利用度的贡献。

• 发表时间: 2006
• 期刊: Int. J. Pharm. 309
• 作者: Irie;M. et al.;Mingji Jin他6名
• 通讯作者: Mingji Jin他6名

PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2

• DOI: 10.1124/mol.104.002212
• 发表时间: 2005-03-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Kato, Y;Sai, Y;Tsuji, A
• 通讯作者: Tsuji, A

Functional characterization of human organic cation transporter OCTN1 single nucleotide polymorphisms in the Japanese population

• DOI: 10.1002/jps.20190
• 发表时间: 2004-12-01
• 期刊: JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 3.8
• 作者: Kawasaki, Y;Kato, Y;Tsuji, A
• 通讯作者: Tsuji, A

Na(+)/H(+) exchanger 3 affects transport property of h(+)/oligopeptide transporter 1.

Na( )/H( ) 交换器 3 影响 h( )/寡肽转运蛋白 1 的转运特性。

• 发表时间: 2005
• 期刊: Drug Metab Pharmacokinet. 20・6
• 作者: Nagamine;T.;Januszko;A.;Ohta;K.;Kaszynski;P.;Endo;Y;Watanabe C et al.
• 通讯作者: Watanabe C et al.

Functional characterization of human organic cation transporter OCIN1 single nucleotide polymorphisms in the Japanese population.

日本人群中人类有机阳离子转运蛋白 OCIN1 单核苷酸多态性的功能特征。

• 发表时间: 2004
• 期刊: J.Pharm.Sci. 93(12)
• 作者: Sakuma K.;Takahashi T.;Watanabe K.;Watanabe;Y.;Yazawa Y.;Chiba R.;Kitagawa Y.;Ma M.;Suresh P.;Juan W.;Kamal F.;Prakash P.;Nagai Y.;Sega T.;Tazawa S.;Kawasaki Y
• 通讯作者: Kawasaki Y