Transporters are a class of more than 300 membrane proteins that regulate how nutrients and drugs enter and leave biological cells. Transporters have validated clinical significance and affect every aspect of drug ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity). Utilizing the full potentials of transporters open new possibilities of designing safer and more efficacious drugs, through improving drug bioavailability, achieving more targeted tissue distribution and reducing adverse drug effects due to drug-drug interactions. Existing transporter assay methods are not able to address the rapidly growing demands for more transporter assays in better model systems. We have demonstrated the feasibility of using a novel transient-expression technology for setting up transporter-specific assays in polarized cell monolayers;this approach could significantly reduce time and cost for developing similar assays using conventional methods, therefore, could notably increase the utilities of transporter proteins in drug discovery and development. The Phase I project is designed to thoroughly examine this assay approach, and to develop and characterize functional assays for 10 therapeutically important transporters. Other advanced assay setups, such as dual-transporter and knock- out/over-expression models, will also be explored during Phase I. Future Phase II project would be to scale up development efforts for building assays for significantly more transporters, and to explore other cell models, such as human primary cultures, in order to build a better transporter assay platform, for improving prediction of drug ADMET properties in the human. 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.
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.
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Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas et al. (2013) Variability in P-glycoprotein inhibitory potency (IC??) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab Dispos 41:1347-66 |
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