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Abstract:

1. This review will explore, from a pharmaceutical industry perspective, the evidence and consequences of transport protein involvement in pharmacokinetic variability and safety of drugs in humans. With the preclinical and clinical evidence available, the transport proteins that are considered to be the most important in respect of pharmacokinetic variability and safety in humans will be highlighted. 2. A large number of transport proteins have been identified, at both the genetic and the cellular level, which have been suggested to play some role in the absorption, distribution or elimination of endogenous, xenobiotic or drug substrates. 3. The weight of evidence suggests that only a small number of transport proteins need to be routinely considered in the drug-discovery setting driven by the magnitude of their impact on tissue distribution, pharmacokinetic variability and drug-drug interactions. 4. For the majority of candidate drugs, an assessment of the role of transporter proteins in their disposition and safety need only be assessed if in vivo properties suggest that active transport is likely to be a significant factor, if transport proteins are implicated in a particular therapeutic target area or if the disposition and safety of a likely co-medication are known to be significantly modulated by transport proteins.

Keywords: Transport proteins; hepatobiliary excretion; brain penetration; drug-drug interactions; polymorphisms; pharmacokinetics; drug discovery and development

Document Type: Research article

DOI: 10.1080/00498250801923855

Affiliations: 1: Mechanism and Extrapolation Technologies, Preclinical Development DMPK, Glaxo Smith Kline, Ware, UK 2: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, UK