In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.

Propylthiouracil reduces the effectiveness of radioiodine treatment in hyperthyroid patients with Graves' disease.

Organic antithyroid drugs used today include propylthiouracil and the mercaptoimidazolines, carbimazole and methimazole. They can be measured with accuracy and in small quantities in serum by gas-liquid chromatography, high performance liquid chromatography and radio-immunoassay. Bioavailability of these drugs varies from 80 to 95%. During absorption carbimazole, which itself is inactive, is completely converted to methimazole. The total volume of distribution is about 40L for methimazole and around 30L for propylthiouracil, which is about 80% protein-bound, while methimazole is virtually non-protein-bound. Drug transfer across the placenta and into breast milk is also higher for the more lipid-soluble methimazole than for propylthiouracil, which is excreted into breast milk only in small quantities so that no harmful effect to the suckling infant is to be expected. Both drugs are concentrated in the thyroid gland, exerting an effect on intrathyroidal iodine metabolism for periods exceeding those in which serum concentrations can be measured. Less than 10% of both drugs is excreted unchanged in the urine, but detailed metabolic pathways are unknown. The half-life of methimazole is 3 to 5 hours with a total clearance of about 200ml/minute. Propylthiouracil has a half-life of 1 to 2 hours with a clearance of around 120ml/min/m2. Some studies have shown an increased rate of metabolism of anti-thyroid drugs in hyperthyroidism, in particular for methimazole. No reliable information exists regarding pharmacokinetics of these agents in renal and hepatic failure or in children. The clearance of propylthiouracil is unchanged in the elderly. Several mechanisms for the inhibiting effect of these agents on intrathyroidal hormone metabolism have been suggested. In contrast to methimazole, propylthiouracil inhibits the peripheral conversion of thyroxine to triiodothyronine. Preliminary dose-response studies with propylthiouracil suggest a peak therapeutic serum concentration of above 4 micrograms/ml in the treatment of thyrotoxicosis. The choice between the antithyroid drugs is based more upon personal preference and experience than on strict pharmacological principles, as no important differences exist between these drugs with regard to the rate of remission or frequency of occurrence of serious adverse reactions.

Clinical Pharmacokinetics of Antithyroid Drugs

The thionamide antithyroid drugs were discovered in large part following serendipitous observations by a number of investigators in the 1940s who found that sulfhydryl-containing compounds were goitrogenic in animals. This prompted Prof. Edwin B Astwood to pioneer the use of these compounds to treat hyperthyroidism in the early 1940s and to develop the more potent and less toxic drugs that are used today. Despite their simple molecular structure and ease of use, many uncertainties remain, including their mechanism(s) of action, clinical role, optimal use in pregnancy and the prediction and prevention of rare but potentially life-threatening adverse reactions. In this review, we summarize the history of the development of these drugs and outline their current role in the clinical management of patients with hyperthyroidism.

/pdf/anniversary-review-antithyroid-drug-therapy-70-years-later-2tt44xszyt.pdf

Anniversary review: Antithyroid drug therapy: 70 years later

Until the 1950’s, when Daniel et al. (18) discovered thyroglobulin (Tg) in the lymph secreted from the thyroid gland of monkeys and rats, T g had been considered a secluded antigen, which by liberation into the circulation by thyroid surgery, radioiodine, or in pathological conditions, would provoke a production of autoantibodies (81). Later, demonstration of Tg in human sera without evidence for antibody response (3, 56) certainly challenged this concept. Discovery of Tg by means of sensitive radioimmunoassays as a normal constituent in human sera (37, 119, reviewed in 120) gave an increasing understanding both of the immunological mechanisms operating in thyroid autoimmunity such as Graves’ and Hashimoto’s diseases and idiopathic myxoedema, and of some aspects of thyroid physiology and pathology in several aspects of the thyroid diseases. Quantitative and sensitive techniques for measurement of thyroglobulin autoantiboides (TgAb) have further contributed to knowledge within this field (76, 94). The present review deals with some of the results obtained during the past decade by use of radioimmunological methods for measuring both T g and TgAb. Emphasis will be placed on the technical problems of interference from T g in the TgAb radioassay (38, 86), and vice versa (38, 102), in relation to interpretation of results in clinical and experimental studies. Furthermore, the use of the Tg-TgAb system as a model for the study of humoral events in autoimmune diseases (35, 38) and some theories on the pathogenesis of autoimmune thyroiditis will be discussed (45, 121, 127). Finally, some of the future aspects of the investigation of this large protein, the first to be discovered as an autoantigen (89), will be mentioned.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1398-9995.1983.tb05081.x

Serum thyroglobulin and thyroglobulin autoantibodies in thyroid diseases. Pathogenic and diagnostic aspects.

The changes occurring in the levels of circulating thyroid microsomal antibody (M-Ab) and antithyroglobulin antibody (Tg-Ab) during antithyroid drug therapy were studied in 32 patients receiving methimazole for Graves’ disease. M-Ab was determined by competitive binding radioassay and Tg-Ab by a sandwich radiometric method. Before treatment 25 subjects (78.1%) had abnormally elevated (≥ 75 U/ml) M-Ab levels. A more than 30% reduction of M-Ab concentration with respect to the pretreatment value was found in 16 (64.0%) of these patients within the first 3–5 months of therapy, in 23 (92.0%) within 8–11 months and in 21 (84.0%) at the end of treatment (16–18 months). No change was found in the 7 patients with initial M-Ab levels < 75 U/ml. The reduction of M-Ab was more pronounced in the patients with good control of thyrotoxicosis than in those who were still hyperthyroid or were rendered hypothyroid during treatment. Twenty-three patients were followed after completion of the course of methimazole therapy, and 13 of them showed relapse of hyperthyroidism. A significant rise of M-Ab with respect to the values observed at the end of treatment occurred in all relapsing patients who had abnormally elevated M-Ab levels before therapy. With one exception, no M-Ab increase was found in the 10 nonrelapsing patients. However, no difference between relapsing and nonrelapsing patients was observed when the M-Ab changes occurring during treatment were considered. A similar trend during and after withdrawal of therapy was noted for Tg-Ab but, because of the relatively small percentage of positive subjects (25%), the results were less conclusive. The present data indicate that methimazole treatment induces a fall of thyroid antibodies in patients with Graves’ disease, and that relapse of hyperthyroidism is associated with an increase of these antibodies. However, the antibody changes occurring during treatment showed no prognostic value in predicting the outcome of therapy.

Changes of circulating thyroid autoantibody levels during and after therapy with methimazole in patients with Graves’ disease

The effect of 6-propyl-2-thiouracil (PTU), and 1-methyl-2-mercaptoimidazole (MMI) on thyroglobulin (Tg) biosynthesis has been studied in vivo and in vitro. In vivo experiments were performed in rats treated for 20 days with PTU or MMI, analyzing soluble and particulate, cold and 125I-labelled, Tg. Thyroglobulin biosynthesis was also investigated by in vitro experiments, incubating thyroid tissue with labelled amino acid and carbohydrate in the presence of antithyroid compounds. It has been found that in vivo antithyroid agents decrease the amount of soluble Tg and increase the proportion of particulate Tg. Tg from treated animals is poorly iodinated being mainly represented by its 12S subunit. In vitro studies demonstrate that PTU and MMI inhibit Tg biosynthesis which is impaired in the polypeptide synthesis as well as in carbohydrate chains addition. Thus the inhibition of the hormonogenetic processes induced by antithyroid treatment leading to a depressed iodinating activity also appears to be related to a significant impairment of the production of the Tg molecule, the specific iodine acceptor.

I. De Ros

Papers

Effects of propylthiouracil and methylmercaptoimidazole on thyroglobulin synthesis.