Kinetics of metabolite formation and elimination in the perfused rat liver preparation: differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin.

Both [14C]phenacetin and [3H]acetaminophen in tracer concentrations were perfused simultaneously once through the rat liver preparation at a constant perfusate flow rate (10 ml/min), and the rates of appearance of [14C]acetaminophen and [3H]acetaminophen in the effluent were compared. The data indicated that the extraction ratio of [14C]acetaminophen derived from [14C]phenacetin was smaller than that of the preformed [3H]acetaminophen added to the input perfusate (exogenously), i.e., the availability of the metabolite formed in situ was higher than the availability obtained when the metabolite was presented in the input blood. The observed availability of the acetaminophen derived from phenacetin was usually greater than that predicted by a "well-stirred" model and less than that predicted by a "parallel tube" model of hepatic drug clearance; the former model describes the liver as a well-stirred compartment with the drug in liver in equilibrium with that in the hepatic venous blood, and the latter model describes the liver as a group of identical and parallel uints with enzymes distributed evenly in hepatocytes lining the tubes. We conclude that the liver may be viewed as an imperfectly mixed compartment with regard to the availability of the metabolite which is generated from a precursor.