Excretory Processes in Toxicology: Drug Transporters in Drug Development

Abstract

Excretory systems play an important role in determining the overall exposure to pharmaceuticals, and efflux and uptake transporters can contribute greatly to drug efficacy and toxicity depending on the physiochemical characteristics of the drug. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have recognized the importance of drug transporters on pharmacokinetics and the potential for drug–drug interactions and have developed guidance for evaluating drug interactions with investigational new drugs. While drug transporters only contribute to a portion of a drug’s absorption, distribution, metabolism, and excretion characteristics, there have been enough important contributions from in vitro and in vivo studies to predict clinical performance. The FDA and EMA have determined that drug interaction studies with the following transporters must be evaluated if there is evidence that the transporter interacts with the investigational drug: P-glycoprotein (Pg-p), breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), OAT3, multidrug and toxin extrusion 1 (MATE1), and MATE2-K. The purpose of this article is to give investigators an overview of these nine transporters in the context of the required drug–drug interaction studies, clinical relevance, the genetic variant (polymorphism) landscape, and preclinical safety assessment considerations.