Transporter-enzyme interplay and the hepatic drug clearance: what have we learned so far?

Introduction: Transporters and enzymes play an important role in absorption, distribution, clearance and elimination of drugs. Areas covered: This review provides an overview of the extended clearance concept and usefulness of extended clearance classification system (ECCS) in early identification of predominant clearance mechanisms. Clinical studies demonstrating transporter-enzyme interplay, challenges in scaling clearance from in vitro systems, utility of animal models and modeling approaches for evaluating hepatic clearance and drug-drug interactions are reviewed. Expert opinion: Clinical evidence exists supporting organic anion transporting peptide (OATP)1B and drug metabolizing enzymes involvement in clearance of ECCS class 1B drugs. Emerging evidence point toward contribution of organic cation transporter (OCT)1 to hepatic uptake of cationic drugs. Although, limited clinical evidence is presented, preclinical studies and modeling suggests organic anion transporter (OAT)2-enzyme interplay in clearance of class 1A drugs. Data from in vitro assays and preclinical models coupled with physiologically based modeling approaches are key for understanding transporter-enzyme interplay, enabling prediction of pharmacokinetics, tissue exposure and drug interactions. Current methodologies incur limitations and emphasis should be placed on the development of physiologically relevant in vitro models and characterize in vivo animal models to inform mechanistic modeling and improve confidence in prospective predictions.