Abstract

The large increase in propranolol (PL) bioavailability when administered with food cannot be entirely explained by a transient increase in hepatic blood flow. A change in metabolic capacity or tissue uptake induced by changes in insulin and/or glucagon associated with food ingestion may contribute to the food effect. This hypothesis was tested in three groups of four isolated, perfused rat livers in the single-pass mode. PL (20 micrograms/ml) was infused to steady state at 30 ml/min for 120 min, then washed out for 30 min. Insulin or glucagon at 2 x 10(-9) M, or saline (control), was introduced at 70 min. Although neither insulin nor saline perturbed effluent PL or metabolite steady-state concentrations, glucagon caused a transient (15-min) reduction in PL, N-deisopropylpropranolol, propranolol glycol, and naphthoxylactic acid, indicating increased PL uptake, but not a change in metabolic activity. PL uptake was 668 +/- 108 micrograms/g liver tissue overall, and additional uptake after initiation of glucagon infusion was significant at 29 +/- 11.6 micrograms/g liver tissue (4% of initial uptake). Although the increase in PL uptake was small under the described conditions, this interaction with glucagon may contribute to the food effect. In this model system, hormonal effects on PL metabolism were not observed.