Chapter 10 - Role of transporters in drug disposition and drug-drug interactions

Abstract

Membrane transporters facilitate the transport of endogenous substances and drugs across cellular membranes in different tissues and play a pivotal role in organs in which absorption, distribution, metabolism, excretion (ADME), and biological/pharmacological action occur. Alteration of transporter function by inhibitors or inducers can result in clinical victims or perpetrators of drug-drug interactions (DDIs). As a result, drug transporters have a great impact on drug disposition, efficacy, and interactions with other drugs. For the evaluation of investigational drug products, regulatory agencies provide guidelines with proposed decision trees to assess DDI potentials for drug labeling. This chapter summarizes drug transporters that have shown evidence of affecting drug disposition or causing DDIs clinically and reviews the current challenges and limitations of transporter DDI assessment while providing information on the state-of-the-art transporter in vitro/in vivo tools that have been developed to support clinical DDI evaluation. The regulatory landscape of evaluating transporter-mediated DDIs is discussed. Additionally, tools to assess transporter liability and various ways of handling potential DDIs in clinical practice are described and exemplified in relation to drugs interacting with drug transporters.