Beyond the ITC White Paper: Emerging Sciences in Drug Transporters and Opportunities for Drug Development

Yurong      Lai; Peng      Hsiao

doi:10.2174/13816128113199990467

Abstract

Over the recent years there has been a greater appreciation in the important roles drug transporters play in drug-drug interactions (DDI), safety and effectiveness of drugs. Notable consequence of this recognition includes the white paper published by the International Transporter Consortium (ITC) and the guidance documents drafted by regulatory agencies for investigating transporter-mediated DDIs during drug development. While DDIs as a result of transporter-mediated alterations in drug absorption, disposition, or excretion are typically undesirable, there are exceptions. When specific transporters selectively regulate the exposure of a drug at the site of action and/or toxicity, the use of these transporters as molecular targets has been proposed as a promising strategy for tissue-selective drug delivery to enhance efficacy or mitigate toxicity. Furthermore, membrane transporters play a pivotal role in the transport of nutrients and endogenous compounds into or out of cells to sustain cell survival. Genetic polymorphism of drug transporters as well as transporterinhibiting drugs can alter the transporter functional activity and/or protein expression, causing transporter-specific diseases. Therefore, investigating drug-transporter interactions is a critical aspect in candidate drug selection, in order to enhance the pharmacological effects and/or prevent the unintended off-target toxicity. The goal of this review is to provide the drug discovery scientists with a cadre of concepts beyond the ITC White Paper that facilitate rational drug design for optimal safety and efficacy. To that end, this review focuses on the following aspects: 1) regulatory landscape on drug transporter-mediated DDIs, 2) transporter related organ toxicity, 3) utility of drug transporters for target organ delivery, and 4) to highlight the diseases known thus far that are associated with variants of transporter genes.

Keywords: Drug transporters, drug-drug interaction, drug induced organ toxicity, tissue-specific exposure, organ targeting, gene polymorphism, intracellular concentration.

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