High-throughput Prediction of Compound Tissue Distribution

描述（由申请人提供）：项目摘要/摘要：拟议研究的目的是开发用于预测药物化合物在人体内分布的工具。目前还没有用于确定化合物组织分布的实验性高通量筛选（HTS）方法。药物化合物被不同组织和器官吸收的倾向影响其是否将达到其作用靶点，是否将引起不期望的副作用，以及因此是否将在临床上可行。高通量的体外方法预测药物化合物在人体内的分布将是新化学实体（NCE）的临床前筛选的重要补充。该建议是开发一种新的方法，用于预测NCE的总分布容积（Vss）和组织间的相对分布，该方法由基于简单荧光脂质体的体外筛选试验和最先进的计算模型的独特组合组成。所提出的方法将用于候选药物的临床前评估，以提供一种标准且具有成本效益的方法来预测候选药物的总体分布和特定组织吸收。项目叙述：预测药物化合物在体内会发生什么是药物开发过程的重要组成部分。我们建议开发新的工具来预测药物化合物在人体中的分布;这些信息将使药物开发人员能够在开发周期的早期确定他们的候选药物是否会达到目标，并帮助他们分析整体化合物的药代动力学。这些工具的实施将降低药物开发的成本，加速药物发现过程。

DESCRIPTION (provided by applicant): Project Summary/Abstract: The aim of the proposed research is to develop tools for the prediction of the distribution of drug compounds in the human body. There is currently no experimental high throughput screening (HTS) method for determining compound tissue distribution. A drug compound's propensity to be taken up by different tissues and organs affects whether it will reach its action target, whether it will cause undesirable side-effects and hence, whether it will be clinically viable. A high-throughput in vitro method for predicting distribution of drug compounds in the human body would be an important addition to pre-clinical screening of new chemical entities (NCEs). This proposal is for the development of a novel method for the prediction for NCEs of the overall volume of distribution (Vss) and the relative distribution among tissues, consisting of a unique combination of simple fluorescent liposome-based in vitro screening assays and state-of-the-art computational models. The proposed method will be used in the pre-clinical evaluation of drug candidates to provide a standard and cost effective way to predict the overall distribution and specific tissue uptake of drug candidates. Project Narrative: Prediction of what will happen to a drug compound in the body is an important part of the drug development process. We are proposing to develop new tools for predicting where in the human body drug compounds will be distributed; this information will allow drug developers to determine early in the development cycle whether their drug candidates will reach their target and aid in their analysis of overall compound pharmacokinetics. Implementation of these tools will reduce the cost of drug development and accelerate the drug discovery process.