In Vitro-in Vivo Extrapolation of Hepatic Metabolism for Different Scenarios - a Toolbox

The extrapolation of metabolism data from in vitro experiments to in vivo clearances can provide useful information in the fields of pharmacokinetics and toxicokinetics. Depending on the purpose, different toxicokinetic models are used, and these different models require the in vivo metabolic information in different forms. In this study, a comprehensive toolbox for in vitro-in vivo extrapolation (IVIVE) of hepatic metabolism is presented addressing a variety of different extrapolation goals: extrapolation to hepatic blood clearance, extrapolation to organ clearance, extrapolation to whole-body clearance, and extrapolation to clearance at the level of hepatocytes. The use of the extrapolated clearances for calculation of extraction efficiencies and the use in physiologically based pharmacokinetic models are discussed. Furthermore, a sensitivity analysis demonstrates which parameters affect the accuracy of the extrapolation results the most, and the presented extrapolation procedure is evaluated by comparison to experimental data from perfused liver experiments.