Furosemide, fenclofenac, diclofenac, mefenamic acid and meclofenamic acid inhibit specific T3 binding in isolated rat hepatic nuclei.

Previous studies with phenytoin (DPH) show that this inhibitor of thyroid hormone binding to plasma proteins also interacts with specific nuclear T3 binding sites. In order to further define the nuclear effects of drugs that inhibit plasma protein binding of thyroid hormones, we assessed furosemide and a number of non-steroidal antiinflammatory drugs using isolated rat liver nuclei. The effects were compared with those of DPH, ipodate and amiodarone. The T3 binding site in isolated nuclei (Ka 1.2 X 10(9)M-1) showed relative affinity triac approximately equal to T3 greater than T4. Drugs were studied over the concentration range 10(-3)-10(-7)M, approximating the known therapeutic total plasma concentrations, in competition with 125I-T3 0.1 nM, expressing inhibition as the percent decrement from maximum specific binding of 125I-T3 in drug vehicle (assay buffer or thanol 1-10%). Specific T3 binding was inhibited by furosemide to 78.8 +/- 3.5% at 2 mM, by fenclofenac to 37.6 +/- 2.8% at 1 mM, by meclofenamic acid to 70.2 +/- 2.4% at 0.1 mM, by mefenamic acid to 60.6 +/- 4.6% at 0.05 mM (each p less than 0.02) and by diclofenac to 87.4 +/- 5.6% at 0.2 mM (p less than 0.05). In comparison, DPH inhibited T3 binding to only 88.1 +/- 0.6% at 0.3 mM, as did calcium ipodate (68 +/- 3.5% at 1 mM, p less than 0.02). Amiodarone (0.3 mM), sodium salicylate (1 mM) and phenylbutazone (0.1 mM) were inactive. In order to achieve a level of nuclear receptor occupancy that approaches in vivo occupancy, the concentration 125I-T3 was increased over the range 0.1-0.5 nM.2+t