A Comprehensive Platform for Transporter Mediated Drug-Drug Interaction Studies

描述(申请人提供)：转运蛋白是一类1000多种膜蛋白，调节营养物质和药物进入和离开生物细胞的方式。转运蛋白已被证实具有临床意义，并影响药物ADME的各个方面(吸收、分布、代谢、消除)，它们还介导药物与药物的相互作用，导致严重的药物不良反应(ADRs)。利用转运体的全部潜力，通过提高药物的生物利用度、实现更有针对性的组织分布以及减少和/或管理DDI引起的不良反应，为设计更安全、更有效的药物开辟了新的可能性。尽管已知许多转运体会影响药物水平，但通常还没有合适的细胞系、特定的转运体抑制剂和预测的计算模型。在拟议的第二阶段研究中，我们将利用第一阶段开发的Opti-Expression技术，通过在人和大鼠身上开发27种重要药物转运体的转运体分析来解决这些未得到满足的需求。此外，通过对1000种处方药与6种高优先级药物摄取转运体的全面筛选，这项研究将为确定潜在的转运体介导的肝脏和肾脏中的DDiS提供基础。重要的是，这些筛选代表了抑制转运蛋白的化合物的最大和最完整的筛选。被确定为潜在转运蛋白抑制剂的化合物可以在后续的临床DDI研究中进行测试。这项研究将导致发现特异性和一般性的抑制剂，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体，并确定临床DDIS的基础机制。目前，还没有数据库或知识库包含有关转运蛋白介导的DDIS的特定大规模信息。这项研究将促进建立一个转运体抑制数据库，该数据库以拟议的筛选研究中获得的数据为基础。这个数据库将成为学术界、工业界和FDA科学家的重要工具。 与公众健康相关：该项目的成功将有助于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间相互作用而产生的不良药物影响来提高药物安全性，从而使公众健康受益。

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.