Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow,plasma and blood cell binding,and the hepatocellular enzymatic activity on hepatic drug clearance

Two commonly used models of hepatic drug clearance are examined. The “well-stirred” model (model I) views the liver as a well-stirred compartment with concentration of drug in the liver in equilibrium with that in the emergent blood. The “parallel tube” model (model II) regards the liver as a series of parallel tubes with enzymes distributed evenly around the tubes and the concentration of drug declines along the length of the tube. Both models are examined under steady-state considerations in the absence of diffusional limitations (cell membranes do not limit the movement of drug molecules). Equations involving the determinants of hepatic drug clearance (hepatic blood flow, fraction of drug in blood unbound, and the hepatocellular enzymatic activity) and various pharmacokinetic parameters are derived. Similarities and differences between the models are explored. Although both models predict similar hepatic drug clearances under a variety of conditions, marked differences between them become apparent in their predictions of the influence of changes in the determinants of drug clearance on various pharmacokinetic parameters.