Chapter 8: Knockout and Humanised Animal Models to Study Membrane Transporters in Drug Development
Published:16 Aug 2016
N. Scheer, X. Chu, L. Salphati, and M. J. Zamek-Gliszczynski, in Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development, ed. G. Nicholls, K. Youdim, G. Nicholls, and K. Youdim, The Royal Society of Chemistry, 2016, vol. 1, ch. 8, pp. 298-332.
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There is increasing recognition that membrane transporters are major determinants of the pharmacokinetics, tissue distribution, efficacy, and safety of drugs and metabolites. In vitro assays combined with static and dynamic translational approaches are powerful tools to predict the risk of transporter related drug interactions with prototypical clinical probe substrate drugs. In contrast, direct extrapolation of in vitro transport data to predict clinical transporter mediated drug disposition remains difficult. Preclinical in vivo studies can provide useful bridging information towards understanding transporter limited or transporter mediated drug absorption, distribution, and excretion by contextualizing the relevance of in vitro substrate findings in terms of in vivo pharmacokinetics. Transporter gene knockout models are particularly useful in this regard and used routinely to define the role of transporters in various aspects of drug disposition. Genetically and liver humanized transporter animal models are emerging tools intended to overcome limitations stemming from species differences in transporter expression and substrate specificity, as well as differences in drug metabolism. This chapter provides an overview of the methods utilized for generating transporter knockout and humanized animals and the models described to date. It discusses the utility, selected case studies, best practice study design, and future directions for the rational application of these animal models to understanding the impact of transporters on pharmacokinetics.