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Clarification of organ specific transport mechanism of druge and its application to regulation of pharmacokinetics and pharmacodynamics

阐明药物的器官特异性转运机制及其在药代动力学和药效学调控中的应用

基本信息

批准号：
07307035
负责人：
TSUJI Akira
金额：
$ 3.07万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

The purpose of this research project is to clarify the organ specific transports of drugs from the view points of organ, cell, molecular and gene levels and to develop novel method for regulation of pharmacokinetics and pharmacodynamics of drugs. The following results were obtained by two years term of this research project consisted of 14 investigators :1.Several evidences were obtained for molecular and biological characteristics of transporters involved in the buccal and intestinal absorption and secretion, renal secretion and reabsorption, hepatic uptake and biliary secretion and in the brain influx and efflux transports. Cloning of transporters of PepT1, PepT2, MCT1, cMOAT,OAT-K1 and OCT2, their transport functions and tissue distribution were clarified. It was also clarified that P-glycoprotein functions as the transport barrier for lipophilic xenobiotics in the intestine and at the blood-brain barrier (BBB). Peptides were confirmed to be taken up by adsorptive-mediated endocytos … More is at the BBB to be delivered into the brain. 2.Improvement of absorption for drugs was achieved by glycosylation, endocytosis across Peyer's patches, iontophoretic method and by absorption enhancers to open tight junction. 3.Uptake of fractionated heparin by hepatocytes and Kupffer cells was clarified to be regulated by the scavenger receptor-mediated and plasma proteins-mediated mechanisms. Liver-specific delivery of drugs, proteins and gene was achieved by using galactosylated technology. Reactive oxygen species, such as superoxide and nitric oxide (NO), were clarified to play critical roles in the pathogenesis of various diseases. To overcome the oxidative stress, synthesized site-directed SOD derivatives were succeeded to deliver the targeting cells. An attractive approach for the antibody-based therapy of solid tumors was proposed and evaluated successfully by use of "vascular targeting" antibody to recognize tumor endothelial cells. 4.Using alpha 1-adrenoreceptor as a model, cloning of the receptors and detection of the tissue localization of the receptor protein were succeeded. It was indicated that uridine receptor plays some role not only in brain but also in peripheral tissues. Pharmacokinetic and pharmacodynamic behaviors for the transport in the brain, receptor binding and analgesic action were analyzed after peptazocine administration in rats. Less

本研究的目的是从器官、细胞、分子和基因水平阐明药物的器官特异性转运，为药物的药代动力学和药效学调控提供新的方法。本研究由14名研究人员组成，历时两年，取得了如下结果：1.对转运蛋白在口腔和肠道的吸收和分泌、肾脏的分泌和重吸收、肝脏的摄取和胆汁的分泌以及脑的流入和外流转运中的分子和生物学特性进行了研究。阐明了PepT1、PepT2、MCT1、cMOAT、OAT-K1和OCT2转运蛋白的克隆、转运功能和组织分布。还阐明了P-糖蛋白在肠道和血脑屏障(BBB)中作为亲脂性外源生物的转运屏障的作用。多肽被吸附介导的内吞…所摄取更多的是在BBB被传递到大脑中。2.通过糖基化、跨Peyer‘s斑片的内吞作用、离子电泳法和通过吸收促进剂打开紧密连接来改善药物的吸收。3.肝细胞和枯否细胞对分级肝素的摄取受清道夫受体和血浆蛋白两种机制的调节。利用半乳糖化技术实现了药物、蛋白质和基因的肝脏特异性递送。超氧化物歧化酶和一氧化氮(NO)等活性氧物种在各种疾病的发病机制中起着关键作用。为了克服氧化应激，合成的定点定向的SOD衍生物被成功地输送到靶向细胞。利用“血管靶向”抗体识别肿瘤内皮细胞，为实体瘤的抗体治疗提供了一种有吸引力的方法，并获得成功评价。4.以α1-肾上腺素受体为模型，成功地克隆了受体，并检测了受体蛋白的组织定位。提示尿苷受体不仅在脑内发挥一定的作用，在外周组织中也有一定的作用。分析了大鼠给药后药物在脑内转运、受体结合和镇痛作用的药代动力学和药效学行为。较少