In vivo study of propranolol and metabolite(s) disposition in rat liver

To investigate the intrahepatic disposition of drugs subjected to the first-pass effect, propranolol (0.002 mg/kg and 5 mg/kg) was injected into the portal vein of rats. At various times the drug was measured in liver homogenate, cytosol, smooth microsomal, and Golgi fractions. The results suggest that hepatic uptake of propranolol is an extremely rapid process and essentially complete, independently of the dose. Effectively at 0.5 min, 70% and 85% of the low and high doses, respectively, were recovered in the liver homogenate. Furthermore following the 0.002-mg/kg dose, 96% of the recovered drug equivalents in the suprahepatic blood consisted of metabolites. An additional experiment demonstrated that the uptake of a 0.002-mg/kg dose of propranolol was not modified by a loading dose of 25 mg/kg. The pattern of propranolol distribution correlated with the intracellular localization of phospholipids and proteins. The amount of propranolol found in subcellular fractions relative to liver homogenate remained constant throughout the study, suggesting a rapid equilibrium. Low doses of propranolol were cleared from the hepatic cells almost completely by biotransformation. However, high doses saturated the metabolic clearance. Propranolol metabolites accumulated preferentially in the cytosol fraction. The intracellular elimination of the metabolites appeared to be a saturable process. The Golgi apparatus does not seem to be involved in the elimination of propranolol or its polar metabolites.