Transporter-Enzyme Interplay Evaluation via Microfluidiic HTS Cell Culture Device

通过微流控 HTS 细胞培养装置评估转运蛋白-酶相互作用

基本信息

批准号：
7429824
负责人：
LESLIE Z BENET
金额：
$ 35.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-02 至 2009-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Because of numerous past failures, it is the belief of many pharmaceutical scientists that animal models are not useful in predicting human DMPK (drug metabolism and pharmacokinetics) and toxicology. This has promoted initiatives to advance NMEs (new molecular entities) into man as soon as possible with a deemphasis of animal work. Although there can be marked advantages to evaluation of NMEs in humans early in drug development, we do not believe that this is the most efficient or most effective way to select the DMPK-optimal molecule from many potential candidate compounds. We hypothesize that the poor predictability of animal models for highly metabolized compounds (approximately 70% of drugs on the market) is due to our nascent understanding of how to incorporate transporters, both absorptive and efflux, into predictive models of drug metabolism, and this lack of understanding of transporter-enzyme interplay renders traditional drug disposition theory simplistic and inadequate, which accounts for the poor predictability. However, most importantly we lack a simple high-throughput preclinical tool to characterize transporter enzyme interplay that conveniently allows human-animal comparisons. In this application, we describe a novel preclinical tool, the microfluidic cell culture biochip in development by the Hurel Corporation and propose studies to test the applicability of this system to address the issues of concern as outlined in 10 specific aims. We will characterize hepatic and enterocyte transporter-enzyme interplay in the Hurel system, initially separately and then combined, utilizing cultured rat and human hepatocytes and enterocytes for Class 1 and Class 2 highly metabolized compounds. These data will be compared with rat liver and intestinal perfusion, rat and human hepatocyte/enterocyte and microsome studies and whole animal iv dosing pharmacokinetics studies carried out predominantly external to this application. A major focus of the work will be to test the concordance of the Hurel device results with the more laborious animal and human studies and to develop models that will allow prediction of animal preclinical DMPK using the Hurel microfluidic cell culture biochips, as well as address the deficiency of our present models of drug elimination that do not adequately consider transporter-enzyme interplay in drug disposition.

描述（由申请人提供）：由于过去的许多失败，许多药物科学家的信念是，动物模型可用于预测人DMPK（药物代谢和药代动力学）和毒理学。这促进了将NME（新分子实体）尽快推向人类的倡议，并视为动物工作。尽管在药物开发早期对NME的评估可能具有明显的优势，但我们认为这是从许多潜在候选化合物中选择DMPK最佳分子的最有效或最有效的方法。我们假设动物模型对高度代谢化合物的可预测性差（市场上约有70％的药物）是由于我们对如何掺入可吸收和外排的方式新生的理解，这些都缺乏药物代谢的预测模型，这是由于我们对药物代谢的预测模型，而这是由于我们对转运蛋白的预测性而言，这是由于我们对化合物的预测性。对转运蛋白酶相互作用的理解使传统的药物处理理论简单化和不足，这说明了可预测性差。但是，最重要的是，我们缺乏一种简单的高通量临床前工具来表征转运蛋白酶相互作用，该酶相互作用便利地可以进行人体 - 动物的比较。在本应用程序中，我们描述了一种新型的临床前工具，即Hurl Corporation在开发中的微流体细胞培养物生物芯片，并建议研究该系统的适用性，以解决10个特定目标中概述的问题。我们将表征Hurel系统中的肝和肠细胞转运蛋白 - 酶相互作用，最初是单独的，然后使用培养的大鼠和人类肝细胞和肠细胞和肠细胞的1类和2类高度代谢化合物。这些数据将与大鼠肝脏和肠道灌注，大鼠和人肝细胞/肠o和微型体研究以及整个动物IV药代动力学研究进行比较。这项工作的主要重点是测试Hurel装置的一致性与更费力的动物和人类研究，并开发模型，可以使用Hurl Microfluidic细胞培养物生物芯片预测动物临床前DMPK，并解决我们目前的消除药物消除模型的缺乏，这些模型没有充分考虑药物处置中的转运蛋白 - 酶相互作用。