Flow dependence of propranolol elimination in perfused rat liver

The effect of experimental variations of the blood flow rate on hepatic elimination of propranolol was studied in livers from 200 g rats perfused in a recirculating system given a constant infusion of propranolol into the reservoir throughout each experiment. This design ensures that, at steady state, the elimination rate of propranolol is the same as the infusion rate of propranolol, and equal to the hepatic blood flow rate multiplied by the hepatic inlet to outlet propranolol concentration difference. Thus, when flow is increased, the concentration difference will decrease, and vice versa. It is currently a matter of debate whether or not this change in concentration difference will influence the outlet substrate concentration. The venous equilibration model (Rowland et al., J. Pharmacokinet. Biopharm. 1: 123-136, 1973) predicts that at a given elimination rate, the outlet concentration is flow-independent, whereas the sinusoidal perfusion model (Bass et al., J. Theor. Biol. 61: 393-410, 1976) predicts that both inlet and outlet concentrations will change. In 13 of 14 experiments, increasing the flow rate (from an average 9 to 14 ml/min) resulted in a decrease of the inlet concentration and elevation of the outlet concentration (each P less than .005). Thus, the data reject the venous equilibration model but are consistent with the sinusoidal perfusion model under the experimental conditions investigated.