Interaction of Furosemide with Serum Thyroxine Binding Sites: In Vivo and in Vitro Studies and Comparison with Other Inhibitors*

Abstract

The diuretic furosemide inhibits serum protein binding of T4 in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [125I]T4 from isolated preparations of T4-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 micrograms/ml furosemide increased the free T4 and free T3 fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [14C]furosemide to TBG was inhibited by unlabeled T4, suggesting that furosemide and T4 share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [125I]T4 (using serum diluted 1:10) from 4.1 +/- 1.0 (+/- SE) to 10.8 +/- 4.3 (P less than 0.01) after 2 h, while decreasing total T3 from 75 +/- 5 to 56 +/- 13 ng/dl (P less than 0.01) and total T4 from 6.7 +/- 0.9 to 4.8 +/- 0.8 micrograms/dl (P less than 0.01) after 5 h. Various ligands inhibited [125I]T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). These studies demonstrate that furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.

Allosteric Modulation of Hormone Release from Thyroxine and Corticosteroid-binding Globulins

“…This allows us to demonstrate unequivocally that although cleavage of the reactive loop in TBG results in a markedly lowered affinity, the cleaved form still binds thyroxine with an affinity that greatly exceeds the binding affinity of intact uncleaved TBG for drugs such as furosemide that are considered to compete in vivo for binding with thyroxine (34). We also show here that cleaved CBG can still effectively complex with cortisol (Table 3).…”

Thyroid hormone replacement for nephrotic syndrome patients with euthyroid sick syndrome: a meta-analysis

“…Massive proteinuria may result in loss of thyroid-binding globulin (TBG) 29 and furosemide can compete for T4-binding sites on TBG, both contributing to lower total T4 and T3 levels. 30 While oxidative stress, psychological pressure and the long-term use of glucocorticoid can inhibit the expression of TSH in pituitary, balancing out the elevated TSH caused by the low levels of serum thyroid hormones, thus making the levels of serum TSH be normal or slightly low. [31][32][33] Yu et al 34 showed that the syndrome was due, in part, to the decreased activity of type I 5 0 -deiodinase (5 0 -DI), the hepatic enzyme that converts T4 to T3.…”

Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen

“…Schwankungen der Jodidzufuhr ausgleichen kann. [33,40,43,46] die Bindung. Auch angeborene TBG-Varianten füh-ren zu einer verminderten Bindungskapazität [23].…”