Jp. Villeneuve et al., CLEARANCE BY THE LIVER IN CIRRHOSIS .3. PROPRANOLOL UPTAKE BY THE ISOLATED-PERFUSED HUMAN LIVER, Canadian journal of physiology and pharmacology, 74(12), 1996, pp. 1327-1332
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 hepati
c uptake of propranolol in isolated perfused livers obtained from pati
ents with cirrhosis at the time of transplantation and from organ dono
rs with normal liver architecture. The kinetics of propranolol transpo
rt in the liver were characterized by means of the multiple-indicator
dilution technique, and the outflow pattern of propranolol in the hepa
tic 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 propranolo
l was decreased in cirrhotics compared with organ donors, and the outf
low profile differed between the two groups. In cirrhotic livers, half
of the propranolol in the outflow consisted of throughput material an
d the other half of returning material; in organ donors, all of the pr
opranolol in the outflow was returning material. In the presence of al
bumin and alpha(1)-acid glycoprotein in the perfusate, about 80-85% of
propranolol was protein bound; removal of albumin and alpha(1)-acid g
lycoprotein from the perfusate in cirrhotic livers resulted in an incr
ease in the free fraction of propranolol, an increase in steady-state
extraction, and a decrease in the throughput component of propranolol
in the outflow. Vile conclude that impaired uptake of protein-bound pr
opranolol, as a result of capillarization and intrahepatic shunts, con
tributes to its impaired elimination in cirrhosis.