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An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation.
European Journal of Pharmaceutical Sciences 2018 October 16
As explained by the free drug theory, the unbound fraction of drug has long been thought to drive the efficacy of a molecule. Thus, the fraction unbound term, or fu , appears in equations for fundamental pharmacokinetic parameters such as clearance, and is used when attempting in vitro to in vivo extrapolation (IVIVE). In recent years though, it has been noted that IVIVE does not always yield accurate predictions, and that some highly protein bound ligands have more efficient uptake than can be explained by their unbound fractions. This review explores the evolution of fu terms included when implementing IVIVE, the concept of protein-facilitated uptake, and the mechanisms that have been proposed to account for facilitated uptake.
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