INVESTIGATIONS ON THE DRUG-PROTEIN IN TERAC TION OF CERTAIN NEW POTENTIAL LOCAL ANAESTHETICS

Generally, plasma proteins owe their binding capacity to the presence of aminoacid units which enter into intra- and intermolecular hydrophobic bonding with a diverse range of endo- and exogenous chemical substances. The intermolecular interactions between the hydrophobic areas of drug molecules and those of plasma proteins play an important role in drug-macromolecular complex formation and stabilization. This largely accounts for the carrier capacity of proteins for lipid soluble drugs. Albumin may be particularly responsible for the binding of local anaesthetics in plasma, but another binding factor may be lipoproteins present in blood cell membranes. Thus, and due to the special importance of the drug-protein binding phenomenon and its influence on the biological response, this investigation has been commenced on the purpose of establishing whether the degree of drug-protein interaction could be correlated with the duration of action of certain new potential local anaesthetics. These are derivatives of 2-phenoxyethyldialkylamine hydrochloride. Equilibrium dialysis, being generally the most reliable of the various methods available, was chosen as a means of determining the extent of drug-protein binding, and bovine serum albumin CBSA) of molecular weight around 70,000 was employed. An ultraviolet assay method was used to measure the concentration of free, unbound local anaesthetic molecules in the protein-free compartment, once equilibrium had been attained. It was found that the affinity of the test compounds for BSA does not parallel their duration of action produced in the guinea pig intradermal wheal test. Moreover, the ability of BSA to bind these local anaesthetics appeared not to depend on the number of binding sites on the protein molecule, but rather on the proportion of :::union:::ised lipophilic species. This suggests that ionic forces probably play no essential part in the binding process.