Molecular properties associated with transporter-mediated drug disposition.

Membrane transporters play a key role in the absorption, distribution, clearance, elimination, and transport of drugs. Understanding the drug properties and structure activity relationships (SAR) for affinity to membrane transporters is critical to optimize clearance and pharmacokinetics during drug design. To facilitate the early identification of clearance mechanism, a framework named the extended clearance classification system (ECCS) was recently introduced. Using in vitro and physicochemical properties that are readily available in early drug discovery, ECCS has been successfully applied to identify major clearance mechanism and to implicate the role of membrane transporters in determining pharmacokinetics. While the crystal structures for most of the drug transporters are currently not available, ligand-based modeling approaches that use information obtained from the structure and molecular properties of the ligands have been applied to associate the drug-related properties and transporter-mediated disposition. The approach allows prospective prediction of transporter both substrate and/or inhibitor affinity and build quantitative structure-activity relationship (QSAR) to enable early optimization of pharmacokinetics, tissue distribution and drug-drug interaction risk. Drug design applications can be further improved through uncovering transporter protein crystal structure and generation of quality data to refine and develop viable predictive models.