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Analysis of the factors governing the elimination route of therapeutic agents

控制治疗药物消除途径的因素分析

基本信息

批准号：
11470509
负责人：
SUGIYAMA Yuichi
金额：
$ 9.22万
依托单位：
Graduate School of Pharmaceutical Sciences, 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：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470509/
关键词：
Transporter Organic anion Biliary excretion Urinary excretion MRP2 MRP3 oatp1 oat3

项目摘要

Therapeutic agents administered to the body are generally eliminated by the metabolism and/or excretion both in the liver and kidney. The elimination route (liver or kidney) of the drugs has been believed to mainly depend on the physicochemical properties of the drugs. However, the recent advance in the molecular biology revealed that many types of drug transporters are expressed in both organs and involved in drug disposition. Therefore, the present study focused on the function of such transporters in vivo to determine the drug elimination route. We have established the gene transfectant systems both for Ntcp and Oatp1 and analyzed their substrate specificity. Many types of therapeutic agents were identified as substrates of Oatp1 whereas Ntcp has the narrow substrate specificity within the bile acids. By comparing the transport activity between the hepatocytes and such transfectants, we have estimated the contribution ratio of Oatp1 to the overall uptake of each substrate by hepatocytes. In this study we also identified new clones, Oat3 and Oat4, which are expressed in the liver. Substrate specificity of Mrp3 which is expressed on the basolateral membrane of the liver was examined. We found that Mrp3 accepts bile acids as substrates and is involved in their efflux from the hepatocytes in the isolated rat liver perfusion system. Cholestatic condition as well as phenobarbital treatment results in the overexpression of Mrp3 which come from at least partially the increase in mRNA level. Since Mrp3 accept many types of organic anions as substrates, these findings imply that the specific transport systems should be considered to be involved in the efflux of drugs from the liver to blood.

给予身体的治疗剂通常通过肝脏和肾脏中的代谢和/或排泄而消除。人们认为药物的消除途径（肝脏或肾脏）主要取决于药物的理化性质。然而，分子生物学的最新进展表明，许多类型的药物转运蛋白在两个器官中表达并参与药物处置。因此，本研究重点关注此类转运蛋白在体内的功能，以确定药物消除途径。我们建立了Ntcp和Oatp1的基因转染系统并分析了它们的底物特异性。许多类型的治疗剂被鉴定为 Oatp1 的底物，而 Ntcp 在胆汁酸内具有狭窄的底物特异性。通过比较肝细胞和此类转染子之间的转运活性，我们估计了Oatp1对肝细胞对每种底物的总体摄取的贡献率。在这项研究中，我们还鉴定了在肝脏中表达的新克隆 Oat3 和 Oat4。检查了在肝脏基底外侧膜上表达的Mrp3的底物特异性。我们发现Mrp3接受胆汁酸作为底物，并参与胆汁酸从离体大鼠肝脏灌注系统中肝细胞的流出。胆汁淤积状态以及苯巴比妥治疗会导致 Mrp3 过度表达，这至少部分来自 mRNA 水平的增加。由于Mrp3接受多种类型的有机阴离子作为底物，这些发现意味着特定的转运系统应被认为参与药物从肝脏到血液的流出。