A Transporter-Based Predictive ADME Platform

描述（由申请人提供）：理想的药物ADME（吸收、处置、代谢和消除）特性是药物安全性和有效性的关键决定因素。不幸的是，较差的ADME和毒性属性导致了比任何其他因素更多的药物失败。迫切需要更好的体外预测ADME工具来增加十年之久的动物研究，这些研究并不总是预测人类的临床结果。该项目的总体目标是确定药物在体外与转运蛋白的相互作用是否可以解释和预测药物在体内的ADME特性，转运蛋白已被证明在药物ADME的各个方面发挥重要作用，以及代谢酶的相互作用和其他药物的物理化学性质。第一阶段的初期工作将首先通过测试一组针对这些转运蛋白的药物，来检查主要肝转运蛋白在药物的肝脏配置中的作用；将建立新的体外模型，研究转运体- cyp相互作用对肝脏药物代谢的影响；最后，将建立体外数据与临床处置和代谢信息之间的相关性。未来的研究将扩展到其他主要组织/器官，目的是在体外转运体研究和其他药物物理化学性质的基础上解释和预测药物ADME特性和药物-药物相互作用（DDI）。

DESCRIPTION (provided by applicant): Desirable drug ADME (Absorption, Disposition, Metabolism and Elimination) properties are key determinants of a drug's to safety and efficacy. Unfortunately, poor ADME and Toxicity attributes have caused more drug failures than any other factors. There is a pressing need for better in vitro predictive ADME tools to augment the decade-old animal studies which do not always predict clinical results in the human. The overall goal of this project is to ascertain whether in vivo drug ADME properties could be explained and predicted based on drugs' in vitro interactions with transporter proteins, which have been demonstrated to play significant roles in every aspect of drug ADME, along with metabolic enzyme interaction and other drug physicochemical properties. The initial Phase I work will start with examining the roles of major liver transporters on hepatic disposition of drugs, through testing a panel of drugs against these transporters; novel in vitro models will be created for studying the effects of transporters-CYP interplay on hepatic drug metabolism; finally, correlations between in vitro data and clinical disposition and metabolism information will be established. Future study would extend the scope to other major tissues/organs with aims to explain and predict drug ADME properties and drug-drug interactions (DDI) based on in vitro transporter studies and other drug physicochemical properties. PUBLIC HEALTH RELEVANCE: Success of this project will benefit public health by facilitating discovery and development of drugs for treating various formidable diseases, particularly CNS diseases and cancer, through enhancing drug efficacy by increasing targeted drug delivery to diseased tissues, and through improving drug safety by reducing adverse drug effects due to unwanted tissue distribution and drug-drug interactions.