The relevance of the facilitated transport hypothesis for in vitro to in vivo extrapolation in toxicology.

Abstract

Issues concerning free and nominal concentrations of toxic compounds in vitro and in vivo are widely recognised. When data from in vitro experiments is extrapolated to in vivo situations it has been understood for a long time that factors like, complex forming and protein binding greatly influence the bio-availability of compounds. The data is normally better explained by extrapolating data using free instead of nominal concentrations in tests. However, it has been shown that in some cases using free concentration results in an under-estimation of the toxic effect. In this study it is reviewed how and to what extent facilitated transport influences the accuracy of extrapolation methods. It will be explained how facilitated transport is defined and how the theory originally designed for metal complexes might be extrapolated to other situations like facilitated transport by proteins. Furthermore it will be discussed that the influence of facilitated transport only has to be taken into account when certain criteria are met. Firstly, there has to be an extracellular ligand for the agent of interest, second the Davison criterium has to be met, thirdly the derived data should be influenced by alterations in kinetics and the ligands should be present or absent in either the in vitro or in vivo situation.