INFLUENCE OF THE ROUTE OF ADMINISTRATION ON THE MEAN HEPATIC EXTRACTION RATIO OF PROPRANOLOL IN THE RAT

The mean hepatic extraction ratio (ER^-) of propranolol was estimated directly by simultaneous measurements of arterial and hepatic venous blood concentrations of the drug following systemic venous and portal venous administration in the rat. The ER^- was greater than 0.9 in the dose range of 2.5 to 12.5 mg/kg following rapid infusion of propranolol into the femoral vein and was not dependent on infusion rate. On the other hand, the ER^- following intraportal constant-rate infusion decreased progressively with increasing dose, although the ER^- at an intraportal dose of 2.5 mg/kg was as high as that found after administration into the femoral vein. In addition, it was found that the ER^- at an intraportal dose of 12.5 mg/kg of propranolol was significantly influenced by infusion rate. The unusual AUC-dose relationship of propranolol previously reported in the rat could be explained on the basis of the present nonlinear hepatic extraction depending on the route and rate of administration which was clarified in vivo. The nonlinear hepatic extraction was further confirmed by determining the remarkably decreased ER^- of 14C-propranolol given intravenously after pretreatment or during portal venous administration of unlabelled propranolol.