Studies on the drug binding of certain novel potential local anaesthetics

One of the many factors affecting the response of an individual to a drug is the modification of its action by tissue and plasma proteins. Plasma proteins can be divided into three categories, viz., fibrinogen, globulins and albumin. Fibrinogen exhibits little reactivity with respect to drugs, being concerned solely with blood clotting, whereas globulins may have affinity for various endogenous compounds. Albumin, which constitutes around 4% of human serum, has the capability to bind reversibly or irreversibly to a wide range of substances. Generally, it has been found that albumins are particularly responsible for binding of local anaesthetics in plasma, but another binding factor may be lipoproteins present in blood cell membranes. Moreover, the transport of local anaesthetics to the site of action in the nerve membrane is influenced by their affinity for proteins present in extracellular fluids either at the site of injection, or surrounding the nerve fibres. Accordingly, systematic investigations on the protein binding characteristics of certain novel potential local anaesthetics was initiated with a view to ascertaining whether the duration of action of local anaesthetics could be correlated with their affinity for protein. The technique of equilibrium dialysis was used for measurements of drug-protein binding. This consists basically of two compartments separated by a semi-permeable cellulose membrane through which only free, unbound drug molecules can diffuse. The results indicate that there is no significant relationship between the extent of drug-protein binding and duration of local anaesthesia produced by these test compounds in the intradermal wheal test on the guinea-pig.