After propranolol administration into the portal vein of doses less than 0.8 mg/kg, little drug appeared in the systemic circulation and hepatic extraction was greater than 95 %. With increasing dose, progressively more drug appeared in the circulation. These findings were confirmed and extended using the perfused rat liver. In a recycling system at an initial -drug concentration of 10 µg/ml, the hepatic clearance of propranolol was equal to liver blood flow (i.e., extraction was 100 %) and the rate of elimination was directly proportional to the volume of the reservoir. Using an open system, propranolol extraction was 98.6 % during a single pass through the perfused liver for 5 min at an inflow concentration of 10 µg/ml. Of that drug removed during the perfusion, 66 % was present unchanged in the liver at the end of the experiment and the liver/perfusate concentration ratio was 170:1. When inflow concentration was increased to 160 µg/ml, extraction fell to 76 %. Of that drug removed, 75 % was present unchanged at the end of the experiment and the liver/perfusate ratio fell to 9.3:1. These studies show that the hepatic extraction of propranolol is concentration-dependent. At low portal venous concentrations, hepatic extraction was essentially 100 % and probably resulted from a high degree of binding of unchanged drug in the liver. With increasing portal venous drug concentrations, this avid hepatic uptake process becomes saturated and hepatic propranolol extraction falls. These findings explain the differences in propranolol disposition according to the route of administration.