The co-administration of lidocaine and propranolol leads to significant drug-drug interactions. Beta-blockers decrease liver perfusion and inhibit the activity of hepatic microsomal lidocaine metabolizing enzymes of the P450_2D subfamily. Hence, there is a resulting reduction in the hepatic breakdown of lidocaine and an increase in its serum concentrations. In this study the ability of propranolol to displace lidocaine from its binding sites in liver tissue has been examined through an in vitro model. Rat liver slices were incubated together with propranolol and/or lidocaine in human serum and the percentage of the bound fraction of lidocaine in the experimental mixture was assessed. The present results indicate that propranolol significantly decreases the binding process of lidocaine in liver tissue. This effect develops only when blood is used as incubation medium and the incubation period lasts 60 min. In conclusion, propranolol can displace lidocaine from liver proteins and therefore the co-administration of the two drugs may increase the free fraction of lidocaine excreted by the liver. However, this result arises from an in virro model and thus further investigation is needed.