TY - JOUR T1 - Navigating Transporter Sciences in Pharmacokinetics Characterization Using the Extended Clearance Classification System JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 729 LP - 739 DO - 10.1124/dmd.117.080044 VL - 46 IS - 5 AU - Ayman F. El-Kattan AU - Manthena V. S. Varma Y1 - 2018/05/01 UR - http://dmd.aspetjournals.org/content/46/5/729.abstract N2 - Membrane transporters play an important role in the absorption, distribution, clearance, and elimination of drugs. Supported by the pharmacokinetics data in human, several transporters including organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE) proteins, P-glycoprotein and breast cancer resistance protein are suggested to be of clinical relevance. An early understanding of the transporter role in drug disposition and clearance allows reliable prediction/evaluation of pharmacokinetics and changes due to drug-drug interactions (DDIs) or genetic polymorphisms. We recently proposed an extended clearance classification system (ECCS) based on simple drug properties (i.e., ionization, permeability, and molecular weight) to predict the predominant clearance mechanism. According to this framework, systemic clearance of class 1B and 3B drugs is likely determined by the OATP-mediated hepatic uptake. Class 3A and 4 drugs, and certain class 3B drugs, are predominantly cleared by renal, wherein, OAT1, OAT3, OCT2, and MATE proteins could contribute to their active renal secretion. Intestinal efflux and uptake transporters largely influence the oral pharmacokinetics of class 3A, 3B, and 4 drugs. We discuss the paradigm of applying the ECCS framework in mapping the role of clinically relevant drug transporters in early discovery and development; thereby implementing the right strategy to allow optimization of drug exposure and evaluation of clinical risk due to DDIs and pharmacogenomics. ER -