In cirrhosis, intrahepatic shunts and capillarization of sinusoids can result in impaired extraction of substrates by the liver irrespective of the metabolic capacity of the liver (intact hepatocyte theory). To evaluate the role of anomalies of uptake in impaired drug disposition, we studied the steady-state hepatic clearance and single-pass hepatic uptake of propranolol in isolated perfused livers obtained from patients with cirrhosis at the time of transplantation and from organ donors with normal liver architecture. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and the outflow pattern of propranolol in the hepatic veins was resolved into throughput material, which had swept past the hepatocytes along with albumin, and returning material, which had entered the cells but returned in the outflow after escaping cellular sequestration and metabolism. The steady-state clearance of propranolol was decreased in cirrhotics compared with organ donors, and the outflow profile differed between the two groups. In cirrhotic livers, half of the propranolol in the outflow consisted of throughput material and the other half of returning material; in organ donors, all of the propranolol in the outflow was returning material. In the presence of albumin and alpha 1-acid glycoprotein in the perfusate, about 80-85% of propranolol was protein bound; removal of albumin and alpha 1-acid glycoprotein from the perfusate it cirrhotic livers resulted in an increase in the free fraction of propranolol, an increase in steady-state extraction, and a decrease in the throughput component of propranolol in the outflow. We conclude that impaired uptake of protein-bound propranolol, as a result of capillarization and intrahepatic shunts, contributes to its impaired elimination in cirrhosis.