How predictive are isolated perfused liver data of in vivo hepatic clearance? A meta-analysis of isolated perfused rat liver data

Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance (CLH). However, to date, IPRL data has not been evaluated for in vivo CLH prediction accuracy. In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in CLH prediction. While the entire dataset poorly predicted CLH (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat CLH (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis. Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current in vitro-in vivo disconnects of hepatic metabolic clearance and improve our methodology for CLH predictions.