Evaluation of New Chemical Entities as Substrates of Liver Transporters in the Pharmaceutical Industry: Response to Regulatory Requirements and Future Steps

This article discusses the evaluation of drug candidates as hepatic transporter substrates. Recently, research on the applications of hepatic transporters in the pharmaceutical industry has improved to meet the requirements of the regulatory guidelines for the evaluation of drug interactions. To identify the risk of transporter-mediated drug-drug interactions at an early stage of drug development, we used a strategy of reviewing the in vivo animal pharmacokinetics and tissue distribution data obtained in the discovery stage together with the in vitro data obtained for regulatory submission. In the context of nonclinical evaluation of new chemical entities as medicines, we believe that transporter studies are emerging as a key strategy to predict their pharmacological and toxicological effects. In combination with the recent progress in systems approaches, the estimation of effective concentrations in the target tissues, by using mathematical models to describe the transporter-mediated distribution and elimination, has enabled us to identify promising compounds for clinical development at the discovery stage.