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)性质是药物安全性和有效性的关键决定因素。不幸的是，不良的ADME和毒性属性导致的药物失败比其他任何因素都多。迫切需要更好的体外预测ADME工具来加强十年前的动物研究，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是否可以根据药物与转运蛋白的体外相互作用来解释和预测体内药物的ADME性质，转运蛋白已被证明在药物ADME的各个方面以及代谢酶相互作用和其他药物的物理化学性质中发挥着重要作用。第一阶段的工作将首先通过测试一组针对主要肝脏转运体的药物来研究主要的肝脏转运体在肝脏药物处置中的作用；将建立新的体外模型来研究转运体-CYP对肝脏药物代谢的影响；最后，体外数据与临床处置和代谢信息之间的关联将被建立。未来的研究将扩展到其他主要组织/器官，旨在基于体外转运体研究和其他药物物理化学性质来解释和预测药物的ADME性质和药物-药物相互作用(DDI)。 与公众健康相关：该项目的成功将有助于发现和开发用于治疗各种严重疾病的药物，特别是中枢神经系统疾病和癌症，通过增加对病变组织的靶向药物输送来提高药物疗效，并通过减少由于不必要的组织分布和药物与药物相互作用而产生的不良药物影响来提高药物安全性，从而造福公众健康。

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.