A Transporter-Based Predictive ADME Platform

基于转运蛋白的预测 ADME 平台

基本信息

批准号：
7804736
负责人：
LESLIE Z BENET
金额：
$ 43.93万
依托单位：
OPTIVIA BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2011-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7804736
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole ABCB1 gene Adverse drug effect Affect Animals Biological Assay Carrier Proteins Categories Cell model Cells Central Nervous System Diseases Classification Clinical Clinical Data Data Development Disease Drug Delivery Systems Drug Efflux Drug Interactions Drug Transport Drug or chemical Tissue Distribution Enzyme Interaction Enzymes Exhibits Failure Future Genes Genetic Polymorphism Goals Hepatic Human In Vitro Literature Liver Malignant Neoplasms Mediating Metabolic Metabolism Modeling Organ POU2F1 gene Permeability Pharmaceutical Preparations Phase Play Property Public Health Role Safety Single Nucleotide Polymorphism Solubility System Testing Tissues Toxic effect Variant Work absorption base drug development drug efficacy drug metabolism improved in vitro Model in vivo metabolic abnormality assessment monolayer novel phase 1 study public health relevance success tool uptake

项目摘要

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.

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 和毒性属性比任何其他因素导致更多的药物失败。迫切需要更好的体外预测 ADME 工具来增强已有十年历史的动物研究，这些研究并不总能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 ADME 特性，转运蛋白已被证明与代谢酶一起在药物 ADME 的各个方面发挥着重要作用相互作用和其他药物理化性质。最初的第一阶段工作将从检查主要肝脏转运蛋白对肝脏药物处置的作用开始，通过测试一组针对这些转运蛋白的药物；将创建新的体外模型来研究转运蛋白-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。未来的研究将范围扩展到其他主要组织/器官，旨在基于体外转运蛋白研究和其他药物理化特性来解释和预测药物 ADME 特性和药物相互作用 (DDI)。公共健康相关性：该项目的成功将有利于公共健康，促进发现和开发用于治疗各种可怕疾病（特别是中枢神经系统疾病和癌症）的药物，通过增加对患病组织的靶向药物输送来提高药物疗效，并通过以下方式提高药物安全性：减少由于不需要的组织分布和药物间相互作用引起的药物不良反应。