The extended clearance model and its use for the interpretation of hepatobiliary elimination data

Hepatic elimination is a function of the interplay between different processes such as sinusoidal uptake,intracellular metabolism, canalicular (biliary) secretion, and sinusoidal efflux. In this review, we outlinehow drugs can be classified according to their in vitro determined clearance mechanisms using theextended clearance model as a reference. The approach enables the determination of the ratedetermininghepatic clearance step. Some successful applications will be highlighted, together with adiscussion on the major consequences for the pharmacokinetics and the drug-drug interaction potential ofdrugs. Special emphasize is put on the role of passive permeability and active transport processes inhepatic elimination.