Clearance by the liver in cirrhosis. II. 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 and compared these values with those of rats with carbon tetrachloride-induced cirrhosis, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and estimates of cellular influx, efflux and sequestration rate constants were obtained with a computer fit to the model of Goresky. The outflow pattern of propranolol in the hepatic veins was then 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 metabolic sequestration. The steady-state extraction of propranolol was significantly decreased in the three experimental groups compared with that in controls, but the outflow profile differed within each group. In cirrhotic animals, influx was markedly decreased and the sequestration 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 propranolol in the outflow was mainly returning material. In rats with acute liver injury, both influx and sequestration rate constants were decreased. 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 compared with the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Gariépy
L
L
Division of Hepatology, Hôpital Saint-Luc, Montréal, Quebec, Canada.
Fenyves
D
D
Kassissia
I
I
Villeneuve
J P
JP
D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology; D066298:In Vitro Techniques; D007201:Indicator Dilution Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011433:Propranolol / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011433:Propranolol; D002746:Chlorpromazine