A Comprehensive Platform for Transporter Mediated Drug-Drug Interaction Studies

描述（由申请人提供）：转运蛋白是一类超过1000种的膜蛋白，它们调节营养物质和药物如何进入和离开生物细胞。转运蛋白影响药物ADME（吸收、分布、代谢、消除）的各个方面，并介导可导致严重药物不良反应（adr）的药物相互作用（ddi）。通过提高药物的生物利用度，实现更有针对性的组织分布，减少和/或管理DDI引起的不良反应，充分利用转运体的潜力，为设计更安全、更有效的药物开辟了新的可能性。尽管已知许多转运蛋白会影响药物水平，但通常没有合适的细胞系、特定的转运蛋白抑制剂和预测计算模型。在拟议的II期研究中，我们将利用i期开发的Opti-Expression技术，对人类和大鼠的27种重要药物转运体进行转运体检测，以解决这些未满足的需求。此外，通过对1000种处方药针对6种高优先级药物摄取转运体的综合筛选，本研究将为鉴定肝脏和肾脏中潜在的转运体介导的ddi提供基础。重要的是，这些筛选代表了最大和最完整的转运蛋白抑制化合物筛选。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抑制剂，这些抑制剂可以用作体外和临床前（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的机制。目前，还没有关于转运体介导的ddi的数据库或知识库。这项研究将有助于建立一个转运体抑制数据库，该数据库是基于在拟议的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的科学家的重要工具。

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.