Mechanisms of cell association of some non-steroidal anti-inflammatory drugs with isolated leucocytes.

In the present study the degree and the mode of association of the radiolabelled drugs acetylsalicylic acid, sodium salicylate, and sodium benzoate with leucocytes were studied in view of the hypothesis that leucocytes are target cells for the anti-inflammatory activity of drugs. The overall association rate of acetylsalicylic acid is larger than that of sodium salicylate and sodium benzoate at 37 degrees, but smaller at 4 degrees. The ratio of the intracellular to the extracellular concentration varied between 1 and 2 for sodium salicylate and sodium benzoate, and between 3 and 6 for acetylsalicylic acid. The intracellular concentrations of these drugs were comparable in red blood cells and polymorphonuclear leucocytes, but lower in mononuclear leucocytes. The association of acetylsalicylic acid and sodium salicylate is markedly increased when the extracellular pH decreases. Lysis of cells decreases the association of acetylsalicylic acid and enhances the association of sodium salicylate and benzoate at 37 degrees twofold. It is suggested that the association of these drugs with leucocytes comprises binding to the membrane and uptake of undissociated species. Phorbol myristate acetate extensively inhibits the intracellular concentration of acetylsalicylic acid, while this inflammatory stimulus tends to increase the intracellular concentration of sodium salicylate. The major metabolites of salicylate enhance cell association of acetylsalicylic acid and salicylic acid. In conclusion, these findings indicate that the tested benzoic acid-like drugs associate with leucocytes in vitro to some extent and that environmental differences, e.g. pH, lysed cells, inflammatory stimuli and metabolites, may determine in vivo the degree of accumulation.