Spectroscopic Analysis of Charge Transfer Complex Formation and Peroxidase Inhibition with Tricyclic Antidepressant Drugs: Potential Anti-thyroid Action.

Abstract

Inspection of the chemical structures of tricyclic antidepressant drugs indicates that they might interfere with the synthesis of thyroid hormones. This iatrogenic potential was demonstrated in vitro by the spectrophotometric detection in both the visible and UV regions of the formation of a complex between antidepressants and iodine. The values of Kc, the formation constant of the drug-iodine complex, were calculated. The concentration of antidepressant which led to a 50% inhibition (IC50) of horseradish peroxidase was also determined. The anti-thyroid activity of drugs can be evaluated from these two parameters, Kc and IC50. The results were compared to those obtained with methimazole, a reference anti-thyroid agent. Antidepressants derived from imipramine appeared to have anti-thyroid activity. This result is now awaiting confirmation in animal experiments.

Thyroid Accumulation and Adverse Effects of Imipramine and Desipramine in Rats after Long-Term Administration

“…0.05), was also found at higher concentrations in the thyroid. As both drugs were characterised in vitro by a high complexation with iodine [11], these findings are in favour of the proposed antithyroid action of these drugs. A supplementary argument could be provided by checking that drug accumulation in the thyroid depends upon the iodine diet regimen: this will be the subject of further studies.…”

“…A second argument, still not demonstrated, would be the accumulation of these drugs in the thyroid, which is a prerequisite to the proposed mechanism of action. As imipramine (IMI) and desipramine (DESI) are characterised by a high constant of iodine complexation in vitro, 4,900 and 2,950 litersW mol -1 [11], the aim of the present study was: (i) to check that these drugs penetrate and accumulate in the thyroid by determining the thyroid and serum concentration-time elimination profiles of IMI and DESI chronically administered to rats, and (ii) to evaluate their respective effects on thyroid hormone serum levels and body weight.…”

Evaluation of the Effects of Clomipramine on Canine Thyroid Function Tests

“…Clomipramine's capacity to donate electrons and impair iodine availability in the thyroid gland has been shown to be 40 times the minimum amount required to produce hypothyroidism, and it has a potency approximately 20% that of methimazole. 17 TCAs also inhibit T 4 production via their effect on thyroid peroxidase (TPO), 17,18 and in vitro studies have demonstrated that clomipramine irreversibly inhibits TPO by binding iodide molecules to the heme portion of the enzyme. 17,37 The concentration of clomipramine required for 50% inhibition of horseradish peroxidase (as a substitute for TPO) was approximately 14 times the plasma clomipramine concentration obtained in dogs treated with clomipramine at 2 mg/kg twice daily.…”

“…11,12 Furthermore, the primary metabolite, desmethylclomipramine, is an inhibitor of norepinephrine reuptake. [13][14][15] TCAs have been extensively documented to inhibit thyroid hormone biosynthesis by altering thyroid follicular cell iodine uptake [16][17][18] and inhibiting thyroid peroxidase. 17,18 In addition, TCAs interfere with the hypothalamic-pituitarythyroid (HPT) axis via the serotonergic and noradrenergic systems, and therefore could lead to a decrease in thyroid stimulating hormone (TSH), thyroxine (T 4 ), and 3,5,3Ј-triiodothyronine (T 3 ) concentrations.…”

Thyroid Function Testing

“…Studies in vitro demonstrate that tricyclic antidepressants, namely, imipramine, desipramine, and clomipramine, have antithyroid effects and act by complexing with iodine and inactivating TPO. 288 Diphenylhydantoin. Diphenylhydantoin (DPH) competes with thyroid hormone binding to TBG.…”