CLEARANCE BY THE LIVER IN CIRRHOSIS .2. CHARACTERIZATION OF PROPRANOLOL UPTAKE WITH THE MULTIPLE-INDICATOR DILUTION TECHNIQUE

We studied the steady-state hepatic extraction and single-pass hepatic uptake of propranolol in isolated perfused livers from normal rats an d compared these values with those of rats with carbon tetrachloride-i nduced cirrhosis, rats treated with chlorpromazine (an inhibitor of pr opranolol metabolism) and rats with acute liver injury. The kinetics o f propranolol transport in the liver were characterized by means of th e multiple-indicator dilution technique, and estimates of cellular inf lux, efflux and sequestration rate constants were obtained with a comp uter fit to the model of Goresky. The outflow pattern of propranolol i n the hepatic veins was then resolved into throughput material, which had swept past the hepatoyctes along with albumin, and returning mater ial, which had entered the cells but returned in the outflow after esc aping metabolic sequestration. The steady-state extraction of proprano lol was significantly decreased in the three experimental groups compa red with that in controls, but the outflow profile differed within eac h group. In cirrhotic animals, influx was markedly decreased and the s equestration rate constant remained unchanged; most of the propranolol in the outflow consisted of throughput material. In rats treated with chlorpromazine, the sequestration rate constant was decreased, and pr opranolol in the outflow was mainly returning material. In rats with a cute liver injury, both influx and sequestration rate constants were d ecreased. Indicator dilution curves for nonsequestered tracers showed a decreased transit time for red blood cells and abnormal diffusion of albumin and sucrose into the space of Disse in cirrhotic rats compare d with the other groups. These results demonstrate that the decreased hepatic extraction of propranolol in cirrhotic rats is due to impaired cellular influx rather than to reduced metabolism. We speculate that the limitation of propranolol cellular entry in cirrhosis is related t o restriction of diffusion of protein-bound propranolol into the space of Disse, to the presence of small intrahepatic shunts or to both