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.
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.
|Wittwer, Matthias B; Zur, Arik A; Khuri, Natalia et al. (2013) Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem 56:781-795|