In vitro binding of lidocaine to liver tissue under the influence of propranolol: Another mechanism of interaction?

Abstract

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.

The influence of clonidine co-administration on the extent of lidocaine protein binding to rat serum and tissues

“…Both drugs are known to possess a higher affinity of binding to alpha-acid glycoprotein than to albumin, but in clinical practice only the amount of the free active fraction is important, since this is responsible for the pharmacological effect. These results are in agreement with previous studies in which co-administration of other cationic drugs was shown to increase the concentration of free lidocaine in serum and tissues (2,9).…”

“…It has been previously demonstrated that lidocaine and propranolol are eliminated via hepatic metabolism (2). Lidocaine, after its absorption, is transported from plasma proteins forming a drug-protein complex, which represents a latent store of the drug.…”

“…The drug binding process involves mainly albumin and alpha-acid glycoprotein (4). Lidocaine, as a cationic molecule (pKa = 7.9), shows stronger binding affinity to alpha-acid glycoprotein than to albumin, and can interact with other cationic drugs, such as propranolol, at the same protein binding site (2).…”

“…Additionally, propranolol significantly reduces the binding of lidocaine to liver proteins through a displacement process. Therefore, co-administration of these two drugs may increase the free fraction of lidocaine excreted by the liver (2).…”

Protein Binding of Drugs

“…β-Blockers decrease liver perfusion and inhibit the activity of hepatic microsomal lidocaine metabolizing enzymes of the P450 2D subfamily, resulting in a reduction in the hepatic breakdown of lidocaine and an increase in its serum concentrations. Propranolol significantly decreases the binding process of lidocaine in liver tissue by displacing it from liver proteins, and therefore the coadministration of the two drugs may increase the free fraction of lidocaine excreted by the liver (Tesseromatis et al, 2007).…”