Introducing the Dynamic Well-stirred Model for Predicting Hepatic Clearance and Extraction Ratio

•Prediction of hepatic clearance is of high importance in pharmaceutical research. It is widely reported that the well-stirred model systematically under predicts hepatic clearance. A dynamic well-stirred model (dWSM) incorporating with dynamic free fraction is introduced and experimentally validated using both highly bound and highly free model drugs. The dynamic model significantly outperforms the WSM in predicting hepatic clearance and liver extraction ratio form in vitro clearance data without systematic under-predictions, highlighting the importance of drug plasma protein binding kinetics in addressing the under-prediction of hepatic clearance by the WSM.