Mechanism of Action of Thioureylene Antithyroid Drugs: Factors Affecting Intrathyroidal Metabolism of Propylthiouracil and Methimazole in Rats*

Publisher Website
Google Scholar
Abstract
Experiments were performed with rats to test the physiological significance of a previously proposed mechanism of action of thioureylene antithyroid drugs, which were derived from results obtained with a model system containing purified thyroid peroxidase. Two features of the previously proposed scheme were tested: the effects of drug dosage and the effects of I deficiency. In the dosage experiments, rats were injected with graded doses of [35S]PTU [6-propyl-2-thiouracil] (0.18-59 .mu.mol) or [35S]MMI [1-methyl-2-mercaptoimidazole] (0.16-18 .mu.mol). Thyroid glands were removed 1 and 6-8 h later and 35S distribution in the homogenates was determined by paper chromatography. Serum samples were also analyzed by the same procedure. From the measured 35S activity in the various components and from the known specific activity of the injected drugs, it was possible to calculate thyroidal concentrations of unchanged drug and drug metabolites. At low doses, thyroidal concentrations of unchanged PTU and MMI significantly exceeded their concentrations in serum, as reported by previous investigators. A major new finding in the present investigation was the observation that intrathyroidal metabolism of PTU and MMI is greatly affected by dosage. Marked inhibition of intrathyroidal drug metabolism was observed at 6-8 h when the dosage was increased from 5.9-18 .mu.mol for [35S]PTU and from 0.88-2.2 .mu.mol for [35S]MMI (per 200 g rat). With increasing dosage, PTU and MMI inhibit their own intrathyroidal metabolism. These dosage effects are similar to results previously reported for in vitro oxidation of PTU and MMI by the thyroid peroxidase system, and they offer support for the physiological significance of the previously proposed scheme. Further evidence for the physiological validity of this scheme was obtained in the experiments with I-deficient rats. As predicted from the in vitro findings, intrathyroidal metabolism of [35S]PTU and [35S]MMI was markedly reduced in rats on low I diet.