SBIR-STTR Award

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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
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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.

Thesaurus Terms:
Absorption;Academia;Active Follow-Up;Address;Adverse Drug Effect;Affect;Animals;Assay;Bioassay;Bioavailability;Biologic Assays;Biologic Availability;Biological;Biological Assay;Biological Availability;Biology;Businesses;Cns Diseases;Cns Neoplasms, Malignant;Cns Disorder;Cancer Of The Cns;Cell Culture Techniques;Cell Line;Cell Lines, Strains;Cell Model;Cellline;Cells;Cellular Model;Central Nervous System Cancer;Central Nervous System Diseases;Central Nervous System Disorders;Clinical;Collection;Comment;Comment (Pt);Comment [publication Type];Commentary;Commentary (Pt);Common Rat Strains;Computer Simulation;Computerized Models;Data;Data Banks;Data Bases;Databank, Electronic;Databanks;Database, Electronic;Databases;Development;Disease;Disorder;Drug Efflux;Drug Interactions;Drug Prescribing;Drug Prescriptions;Drug Side Effects;Drug Or Chemical Tissue Distribution;Drugs;Editorial Comment;Editorial Comment (Pt);Enzymes;Epithelial Cells;Excretory Function;Fees;Goals;Housing;Human;Human, General;Ic50;In Vitro;Industry;Inhibitory Concentration 50;Intermediary Metabolism;Investigators;Kidney;Knowledge;Lead;Left;Legal Patent;Libraries;Liver;Metbl;Malignant Tumor Of The Cns;Malignant Tumor Of The Central Nervous System;Malignant Neoplasm Of Central Nervous System;Mammals, Rats;Man (Taxonomy);Man, Modern;Marketing;Mathematical Model Simulation;Mathematical Models And Simulations;Mediating;Mediator;Mediator Of Activation;Mediator Of Activation Protein;Medication;Membrane Proteins;Membrane Transport Proteins;Membrane Transporters;Membrane-Associated Proteins;Metabolic Processes;Metabolism;Methods;Modeling;Models, Computer;Nutrient;Oct1;Oct2;Otf1;Otf2;Ortholog;Orthologous Gene;Pou2f1;Pou2f1 Gene;Pou2f2;Pou2f2 Gene;Prov;Patents;Pb Element;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacology;Phase;Physiologic Availability;Play;Position;Positioning Attribute;Prescriptions, Drug;Process Of Absorption;Provider;Public Health;Published Comment;Rat;Rattus;Reaction;Reagent;Research;Research Personnel;Researchers;Role;Safety;Scientist;Screening Procedure;Services;Simulation, Computer Based;Surface Proteins;System;System, Loinc Axis 4;Technology;Testing;Tissue Distribution;Update;Urinary System, Kidney;Viewpoint;Viewpoint (Pt);Absorption;Assay Development;Base;Bioavailability Of Drug;Body System, Hepatic;Clinical Data Repository;Clinical Data Warehouse;Clinical Significance;Clinically Significant;Computational Modeling;Computational Models;Computational Simulation;Computer Based Models;Computerized Modeling;Computerized Simulation;Cultured Cell Line;Data Repository;Design;Designing;Disease /Disorder;Disease/Disorder;Drug /Agent;Drug Adverse Effect;Drug Detection;Drug Testing;Drug/Agent;Excretion;Follow-Up;Heavy Metal Pb;Heavy Metal Lead;Improved;In Silico;In Vitro Assay;In Vivo;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Knowledge Base;Library;Model;Organ System, Hepatic;Phase 2 Study;Polarized Cell;Pre-Clinical;Preclinical;Public Health Medicine (Field);Relational Database;Renal;Screening;Screenings;Social Role;Success;Tool;Uptake;Virtual Simulation