Influence of Uremia and Hemodialysis on the Plasma Protein Binding of Tolmetin

Binding of the nonsteroidal anti-inflammatory drug, tolmetin, to plasma from uremic patients before hemodialysis and from healthy subjects was compared using micro-equilibrium dialysis techniques. The percent age of free tolmetin was 2–15 times greater in plasma from uremic patients (1.33–3.08%) than in plasma from healthy volunteers (0.37–0.63%) at all three concentrations of the drug studied (0.5, 5 and 50μg/ml). The reduced plasma binding of tolmetin in plasma from uremic patients was associated with significantly higher dissociation constants for the high-affinity tolmetin binding site on plasma albumin. When added at concentrations of 2.0 mM oleic, stearic and palmitic acids, 3 representative nonesterified fatty acids (NEFA) were found to significantly enhance tolmetin binding to plasma proteins. No differences in total plasma NEFA concentrations were observed between uremic patients before hemodialysis and healthy subjects. However, higher total NEFA concentrations in plasma from uremic patients after hemodialysis were accompanied by increased tolmetin binding. Possible NEFA effects on tolmetin binding could not be dissociated from other influences, such as the removal of endogenous binding inhibitors during hemodialysis.