A Comprehensive Platform for Transporter Mediated Drug-Drug Interaction Studies

转运蛋白介导的药物相互作用研究的综合平台

• 批准号: 8124827
• 负责人: KATHLEEN M GIACOMINI
• 金额: $ 92.41万
• 依托单位: OPTIVIA BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124827
• 关键词: Academia; Address; Adverse drug effect; Affect; Animals; Biological; Biological Assay; Biological Availability; Biology; Businesses; Cell Culture Techniques; Cell Line; Cell model; Cells; Central Nervous System Diseases; Clinical; Collection; Computer Simulation; Data; Databases; Development; Disease; Drug Efflux; Drug Interactions; Drug Prescriptions; Drug or chemical Tissue Distribution; Enzymes; Epithelial Cells; Excretory function; Fees; Goals; Housing; Human; In Vitro; Industry; Inhibitory Concentration 50; Kidney; Knowledge; Lead; Left; Legal patent; Libraries; Liver; Malignant neoplasm of central nervous system; Marketing; Mediating; Mediator of activation protein; Membrane Proteins; Membrane Transport Proteins; Metabolism; Methods; Modeling; Nutrient; Orthologous Gene; POU2F1 gene; POU2F2 gene; Pharmaceutical Preparations; Pharmacology; Phase; Play; Positioning Attribute; Provider; Public Health; Published Comment; Rattus; Reaction; Reagent; Research; Research Personnel; Role; Safety; Scientist; Screening procedure; Services; System; Technology; Testing; Update; absorption; assay development; base; clinically significant; design; drug testing; follow-up; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; knowledge base; phase 2 study; polarized cell; pre-clinical; success; tool; uptake

DESCRIPTION (provided by applicant): Transporters are a class of more than 1000 membrane proteins that regulate how nutrients and drugs enter and leave biological cells. Transporters have validated clinical significance and affect every aspect of drug ADME (Absorption, Distribution, Metabolism, Elimination), and they also mediate drug-drug interactions (DDIs) that can lead to serious Adverse Drug Reactions (ADRs). Utilizing the full potentials of transporters opens new possibilities of designing safer and more efficacious drugs, through improving drug bioavailability, achieving more targeted tissue distribution and reducing and/or managing ADRs due to DDI. Despite that many transporters are known to influence drug levels, suitable cell lines, specific transporter inhibitors, and predictive computational models are not generally available. In the proposed Phase II studies we will address these unmet needs by developing transporter assays for 27 important drug transporters in humans and rats, using the Opti-Expression technology developed in Phase I. In addition, through comprehensive screening of 1000 prescription drugs against 6 high priority drug uptake transporters, this research will provide a basis for identification of potential transporter-mediated DDIs in the liver and kidney. Importantly, these screens represent the largest and most complete screen of compounds for inhibition of transporters. Compounds identified as potential transporter inhibitors can be tested in follow-up clinical DDI studies. The research will lead to the discovery of specific and general inhibitors that can be used as tools in in vitro and pre-clinical (as well as clinical) in vivo studies to identify transporters involved in drug absorption and disposition, and to determine the mechanisms that underlie clinical DDIs. Currently, there is no database or knowledgebase that houses specific large-scale information on transporter mediated DDIs. This study will facilitate the establishment of a transporter inhibition database, which is based on the data obtained in the proposed screening studies. This database will be an important tool for scientists in academia, industry and at the FDA. PUBLIC HEALTH RELEVANCE: Success of this project will benefit public health by facilitating discovery and development of more efficacious drugs for treating various formidable diseases, particularly CNS diseases and cancer, and by improving drug safety through reducing adverse drug effects due to unwanted tissue distribution and drug-drug interactions.

描述（由申请人提供）：转运蛋白是一类超过1000种膜蛋白，调节营养物质和药物如何进入和离开生物细胞。转运蛋白具有经验证的临床意义，影响药物ADME（吸收、分布、代谢、消除）的各个方面，并且它们还介导可导致严重药物不良反应（ADR）的药物相互作用（DDI）。利用转运蛋白的全部潜力，通过提高药物生物利用度，实现更靶向的组织分布以及减少和/或管理DDI引起的ADR，为设计更安全和更有效的药物开辟了新的可能性。尽管已知许多转运蛋白会影响药物水平，但通常无法获得合适的细胞系、特异性转运蛋白抑制剂和预测性计算模型。在拟定的II期研究中，我们将通过使用I期开发的Opti-Expression技术开发人类和大鼠中27种重要药物转运蛋白的转运蛋白测定来解决这些未满足的需求。此外，通过针对6种高优先级药物摄取转运蛋白对1000种处方药进行全面筛选，本研究将为识别肝脏和肾脏中潜在的转运蛋白介导的DDI提供基础。重要的是，这些筛选代表了用于抑制转运蛋白的化合物的最大和最完整的筛选。可在后续临床DDI研究中检测被确定为潜在转运蛋白抑制剂的化合物。该研究将导致发现特异性和一般抑制剂，可用作体外和临床前（以及临床）体内研究的工具，以确定参与药物吸收和处置的转运蛋白，并确定临床DDI的基础机制。目前，还没有数据库或知识库来存储关于转运蛋白介导的DDI的特定大规模信息。本研究将有助于建立转运蛋白抑制数据库，该数据库基于拟定筛选研究中获得的数据。该数据库将成为学术界、工业界和FDA科学家的重要工具。 公共卫生相关性：该项目的成功将有利于公共卫生，促进发现和开发更有效的药物来治疗各种可怕的疾病，特别是中枢神经系统疾病和癌症，并通过减少由于不必要的组织分布和药物相互作用引起的药物不良反应来提高药物安全性。