Theoretical analysis of the binding of salicylate by human serum albumin: The relationship between free and bound drug and therapeutic levels

Abstract

Summary The binding of salicylate by human serum albumin was analyzed by use of a computer program using previously published association constants and binding capacities for the two sets of binding sites on the protein. The analysis consisted of computing free and bound salicylate for a range of therapeutic and toxic concentrations from 181 to 7246 µmole/L (25 to 1000 mg/L). At low and therapeutic levels the total amount of bound drug would exceed the amount of free drug. At higher levels, which included therapeutic and toxic ranges, the amount of free drug would equal or exceed the amount of bound salicylate. At low levels of drug in the plasma, up to 2000 µmole/L the high affinity sites (Site 1), would bind most of the drug, but as the concentration of drug increased this site would approach saturation and the low affinity Site 2 would bind increasing amounts of salicylate. At high salicylate levels the amount of drug bound by the low affinity sites would exceed the amount bound by the high affinity sites. Computation also showed that when the total amount of protein in the analysis was reduced, from 5,4,3 to 2 gm%, as in hypoalbuminemia, the total amount of drug bound by the protein would decrease and the quantity of free drug would increase. The amount of drug bound by each of the two sets of sites also fell as the concentration of protein decreased. Some of the possible clinical implications of these findings are discussed.