Salsalate and salicylate binding to and their displacement of thyroxine from thyroxine-binding globulin, transthyretin, and albumin

Salsalate and its metabolite salicylate are inhibitors of thyroid hormone b inding to serum transport proteins and reduce serum total thyroxine (T-4) a nd triiodothyronine (T-3) in vivo. The present study is the first to examin e and compare salsalate and salicylate binding to human thyroxine-binding g lobulin (TBG), transthyretin (TTR), albumin (ALB), and whole human serum, a nd displacement by salsalate and salicylate of T-4 from isolated TBG, TTR, ALE. Salsalate and salicylate binding were studied by ultrafiltration at sa lsalate concentrations of 0.24-1.16 mM (62-300 mu g/mL) and salicylate conc entrations of 0.0375-2.25 mM (6.0-360 mu g/mL). T-4 displacement by salsala te and salicylate from TBG, TTR, and ALE was studied by equilibrium dialysi s at salsalate concentrations of 0 to 1.52 mM (0-393 mu g/mL) and salicylat e concentrations of 0 to 60 mM (0-9600 mu g/mL). In normal human serum, 95% of salsalate and 76% of salicylate were protein-bound. In the presence of isolated ALE, 89% of salsalate and 64% of salicylate were ALB-bound. Both s alsalate and salicylate inhibited T-4 binding to all 3 major T-4 binding pr oteins. Both displaced proportionately more T-4 from TBG compared with TTR and ALB. The principal site to which both salsalate and salicylate in serum is bound (ALB) is different from the principal site from which they displa ce T-4 (TBG). Salsalate potency in displacing T-4 from TBG and ALB was appr oximately 100-fold greater than salicylate potency.