Inhibition of thyroxine binding to serum proteins by fenclofenac and related compounds

The anti-inflammatory drug fenclofenac lowers the serum concentrations of thyroxine (T4) and triidothyronine (T3) in subjects taking a regular dose of 600 mg twice daily. In eight male volunteers the concentration of T4 in serum was reduced to almost a third of the pre-treatment value while the concentration of T3 fell by about a half. The interaction of fenclofenac, and related compounds, while the thyroid hormone binding proteins of serum was studied in vitro by equilibrium dialysis with measurement of the concentrations of the free T4 and T3 in the dialysate by immunoassay. Fenclofenac, at a concentration of 100 mg/l (of the order achieved therapeutically), increased the concentrations of free T4 and by 131% and free T3 by 62%. The related compounds which increased the free hormone concentrations (although at higher concentrations than achieved during therapy) include diclofenac, monohydroxyfenclofenac and dihydroxyfenclofenac. A second in vitro method was used to study the interaction of these drugs with isolated thyroxine-binding globulin (TBG). An antiserum to TBG, coupled to Sephadex particles, was used to isolate TGB from other serum proteins. The effect of the different drugs on the binding of T4 by the immobilised TBG was then measured. These compounds competitively inhibit the binding of T4 by TBG, and for each an inhibitor constant (Ki) was determined.