Drug Competition for Thyroxine Binding to Transthyretin (Prealbumin): Comparison with Effects on Thyroxine-Binding Globulin*

Abstract

We examined the effect of 26 drugs on T4 binding to transthyretin (TTR; prealbumin) and T4-binding globulin (TBG) by determining their ability to inhibit [125I]T4 binding to TTR isolated from normal human plasma and to serum diluted 1:10,000, respectively. The hierarchies for drug inhibition of T4 binding differed greatly for these two proteins. Relative to T4, the drugs were much more potent inhibitors of [125I]T4 binding to TTR than to TBG. Compounds of the anthranilic acid class, such as flufenamic, meclofenamic, and mefenamic acids, interacted particularly strongly with TTR. Flufenamic acid was more potent than T4 itself in inhibiting [125I]T4 binding [175 +/- 17% (+/- SD); cf. T4; n = 3; P less than 0.001], while mefenamic acid, diflunisal, and meclofenamic acid were 20-26% as potent as T4 in their interaction with TTR. The reactivity of diclofenac, fenclofenac, indomethacin, sulindac, and the diuretic ethacrynic acid was 0.8-2.1% relative to that of T4. In contrast, furosemide, the drug most highly reactive with TBG, was only 0.11 +/- 0.03% (n = 7) as potent as T4, followed by meclofenamic acid greater than mefenamic acid greater than fenclofenac greater than flufenamic acid greater than diflunisal greater than milrinone. Aspirin and sodium salicylate were, respectively, 0.05% and 0.20% as active as unlabeled T4 as inhibitors of [125I]T4 binding to TTR, but these compounds had only 3-4 x 10(-6)% of the activity of T4 for TBG binding. Diphenylhydantoin had no detectable effect on T4 binding to TTR and was 2.9 x 10(-4)% as reactive as T4 with TBG. Amiodarone did not interact with either binding site. Drug interactions with TTR may be important when this protein becomes a major circulating T4-binding protein, as in patients with complete or partial TBG deficiency, or when serum T4 is markedly elevated. Such interactions may also be important where TTR is the dominant tissue T4-binding protein, as in the choroid plexus. In addition, the drug competitors described here may be useful as probes to further define the structural basis for specific ligand interactions with different classes of T4-binding sites.

Nonthyroidal illnesses syndrome in full-term newborns with sepsis

“…In low concentrations, 3 µmol/L, it does not show any effect on the hormones, but in high doses, of 30 µmol/L, it increases free T4 (33,34).…”

Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma

“…Because these compounds are already approved by the Food and Drug Administration, they could easily be evaluated in human clinical trials for another indication if they proved to be selective TTR binders in human plasma. However, none of the NSAIDs exhibited significant selectivity for binding TTR in human plasma at a concentration of 10.8 M (Table 1), although most exhibit a submicromolar K d (37,50). The most selective NSAIDs, flufenamic acid (1) and mefenamic acid (2), only had 0.2 eq of a maximum of 2 molar eq bound to TTR.…”

Fatores Interferentes na Interpretação de Dosagens Laboratoriais no Diagnóstico de Hiper e Hipotireoidismo

“…As principais drogas que deslocam T 4 da TBG são os salicilatos, fenclofenaco, fenitoína, carbamazepina e furosemide. Os salicilatos aumentam a fração de T 4 livre em até 100% e a carbamazepina e o furosemide em cerca de 30% (146)(147)(148). O potencial inibitório vai depender da concentração da droga, de sua meia-vida, fração livre e da sua afinidade pela TBG (92,146).…”