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

Ewen Downie Metabolic Unit, Alfred Hospital, Melbourne 3181, and the Victorian College of Pharmacy (J.G.H., D.J.C.) Parkville 3052, Victoria, Australia

Address all correspondence and requests for reprints to: J. R. Stockigt, M.D., F.R.A.C.P., Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Victoria 3181, Australia.

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 < 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 > mefenamic acid > fenclofenac > flufenamic acid > diflunisal > 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.

^* Presented in part at the 15th Meeting of the European Thyroid Association, Stockholm, Sweden, July 1986. This work was supported in part by grants from the National Health and Medical Research Council of Australia.

Received October 12, 1988.

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