Propylthiouracil (PTU) Pharmacology in the Rat,II. Effects of PTU on Thyroid Function*

Abstract

Using a sensitive and specific RIA for propylthiouracil (PTU), we examined the effects of short term (1 week) and long term (1 month) PTU treatment on thyroid function in the rat, and correlated changes in thyroid function with serum and thyroid PTU levels. After 1 week, dose-dependent decreases in thyroid PBI, serum T4, and serum T3 were observed, with concomitant elevations in the serum rT3 to T4 ratio and serum TSH. Fifty percent suppression of thyroid PBI occurred at a PTU concentration in the drinking water of 0.0005% (ED50), with concomitant serum and thyroid PTU levels of 0.3 micrograms/ml and 300 ng/thyroid, respectively. After 1 month of PTU, serum T4 values were lower than after 1 week of treatment for all PTU concentrations, but values for the other thyroid functional variables were similar to those in the 1 week group at comparable PTU dosage. The PTU dose-response curve for thyroid PBI was similar to that seen after 1 week of treatment, with an ED50 of 0.0004%. After discontinuation of PTU treatment, PTU disappeared from serum in a biexponential fashion, with an early rapid distribution phase (t 1/2 = approximately 4 h) and a second slower elimination phase (t 1/2 = approximately 2.6 days). In the thyroid, an initial increase in PTU content was seen up to 18 h after PTU withdrawal; thereafter, thyroid PTU declined linearly, with a t 1/2 of 1.4 days in both groups. After PTU withdrawal, thyroid PBI recovered with a t 1/2 of 1.09 days after 1 week on PTU, but recovery was prolonged (t 1/2 = 2.8 days) after 1 month of treatment. Log thyroid PTU and log thyroid PBI were linearly related after PTU withdrawal (r = 0.97; P less than 0.001) after 1 week but not after 1 month. Serum T4 and serum T3 remained below control values for 2 days, but then rapidly normalized, with T3 values rising transiently above the control value. This rebound occurred at a time when PTU was still present within the thyroid, before thyroid PBI had returned to baseline. These data indicate a close inverse relationship between PTU dose and both thyroid hormone biosynthesis and peripheral T4 deiodination. In addition, short and long term PTU treatments have quantitatively similar effects on thyroid function, although recovery of thyroid function is prolonged after long term treatment. The biexponential disappearance of PTU from the serum is compatible with a two-compartment model of PTU distribution. The early increase in thyroid PTU after drug withdrawal is suggestive of an inhibitory effect of PTU upon its own uptake by the thyroid, whereas the faster disappearance of PTU from the thyroid than from serum is consistent with intrathyroid drug metabolism.

Synaptosomal T3 Content in Cerebral Cortex of Adult Rat in Different Thyroidal States

“…Hypothyroid condition showed an appreciable decline in both serum T4 and T3 level in rats in a usual way as found by other investigators (Larsen and Frumess 1977;Leonard et al 1981;Cooper et al 1983). Although it has been shown earlier that in hypothyroid condition, the whole brain, or different regions of the brain, maintain similar levels of T 3 compared to the euthyroid control rats through increased activity of 5'-deiodinase type II (S'D-II), and corresponding high fractional rate of T4 to T3 conversion (Obregon et al 1978;Vigoroux et al 1979;Crantz and Larsen 1980;Kaplan and Yaskoski 1980;Leonard et al 1981;Leonard et al 1984;Morreale de Escobar et al 1988;St Germain et al 1988;Escobar del Rey 1989;Serrano-Lozano et al 1991), insufficient evidence is available except for a few recent reports (Sarkar and Ray 1992b;Mason et al 1993) to quantitate the synaptosomal concentration of thyroid hormone.…”

Possible Influence of Dopaminergic Receptor in Maintenance of Thyroid Hormone Homeostasis: A Study in Adult Rat Brain

“…In our study, the alterations in serum total T4 and T3 levels observed on Day '2' and Day '20' of PTU treatment were typical of peripheral hypothyroidism involving hypothalamo-pituitary-thyroid axis [6,16]. There were no changes in serum total T4 and T3 concentrations when the dopaminergic agonist, bromocryptine (BROMO), and antagonist, haloperidol (HALO), were treated to animals, either alone or in combination with PTU, on Day '2' and Day '20'.…”

Premature Rats Treated with Propylthiouracil Show Enhanced Pulmonary Antioxidant Enzyme Gene Expression and Improved Survival during Prolonged Exposure to Hyperoxia

“…The control group received drinking water not containing PTU. This regimen has been used previously by others and has been shown to be effective in inhibiting thyroid hormone synthesis without influencing litter size or viability (6). The procedures and dosage of PTU were identical to those used in previously reported full-term newborn rat studies from our laboratories [calculated maternal dose of PTU .-: 30 mglkgld (approximately twice the orally administered clinical dosage)].…”