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

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Propylthiouracil (PTU) Pharmacology in the Rat, II. Effects of PTU on Thyroid Function* 0013-7227/83/1133-0921$02.00/0 Endocrinology Vol. 113, No. 3 Copyright© 1983 by The Endocrine Society Printed in U.S.A. Propylthiouracil (PTU) Pharmacology in the Rat, II. Effects of PTU on Thyroid Function* DAVID S. COOPER,t J. DAVID KIEFFER, RACHELLE HALPERN, VELIA SAXE, HEIDI MOVER, FARAHE MALOOF, AND E. CHESTER RIDGWAY Thyroid Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 ABSTRACT. Using a sensitive and specific RIA for propyl- in both groups. thiouracil (PTU), we examined the effects of short term (1 week) After PTU withdrawal, thyroid PBI recovered with a ti/2 of and long term (1 month) PTU treatment on thyroid function in 1.09 days after 1 week on PTU, but recovery was prolonged (ti/2 the rat, and correlated changes in thyroid function with serum = 2.8 days) after 1 month of treatment. Log thyroid PTU and and thyroid PTU levels. After 1 week, dose-dependent decreases log thyroid PBI were linearly related after PTU withdrawal (r in thyroid PBI, serum T4, and serum T3 were observed, with = 0.97; P < 0.001) after 1 week but not after 1 month. Serum T4 concomitant elevations in the serum rT3 to T4 ratio and serum and serum T3 remained below control values for 2 days, but then TSH. Fifty percent suppression of thyroid PBI occurred at a rapidly normalized, with T3 values rising transiently above the PTU concentration in the drinking water of 0.0005% (ED50), control value. This rebound occurred at a time when PTU was with concomitant serum and thyroid PTU levels of 0.3 jtg/ml still present within the thyroid, before thyroid PBI had returned and 300 ng/thyroid, respectively. After 1 month of PTU, serum to baseline. T4 values were lower than after 1 week of treatment for all PTU These data indicate a close inverse relationship between PTU concentrations, but values for the other thyroid functional var- dose and both thyroid hormone biosynthesis and peripheral T4 iables were similar to those in the 1 week group at comparable deiodination. In addition, short and long term PTU treatments PTU dosage. The PTU dose-response curve for thyroid PBI was have quantitatively similar effects on thyroid function, although similar to that seen after 1 week of treatment, with an ED50 of recovery of thyroid function is prolonged after long term treat- 0.0004%. ment. The biexponential disappearance of PTU from the serum After discontinuation of PTU treatment, PTU disappeared is compatible with a two-compartment model of PTU distribu- from serum in a biexponential fashion, with an early rapid tion. The early increase in thyroid PTU after drug withdrawal distribution phase (ti/2 = ~4 h) and a second slower elimination is suggestive of an inhibitory effect of PTU upon its own uptake phase (ti/2 = ~2.6 days). In the thyroid, an initial increase in by the thyroid, whereas the faster disappearance of PTU from PTU content was seen up to 18 h after PTU withdrawal; the thyroid than from serum is consistent with intrathyroid drug thereafter, thyroid PTU declined linearly, with a ti/2 of 1.4 days metabolism. {Endocrinology 113: 921, 1983) HE in vivo pharmacology of the antithyroid drug of thyroid function. In addition, thyroid recovery pat- Tpropylthiouracil (PTU) in the rat has been studied terns after discontinuation of short and long term regi- by a large number of investigators (1-17). Most phar- mens have been examined. In a companion study (18), macokinetic studies, however, have involved either single we have described in detail the development and valida- injections of radiolabeled PTU or short treatment tion of the PTU RIA used for the present studies, and courses (<1 week) with unlabeled PTU. Although im- have provided data concerning serum and thyroid PTU portant information has been gained from these studies, levels after 1 week and 1 month of treatment. they provide limited insight into the effects of long term PTU treatment on thyroid function. The present inves- Materials and Methods tigations were conducted to explore more fully the effects Outbred male CD rats (Charles River Breeding Laboratories, of different durations of PTU exposure on various indices Wilmington, MA), weighing 200-250 g, were used for all studies. The conditions of animal maintenance were similar to those Received January 4,1983. reported previously (19). The rats were fed a regular diet Address requests for reprints to: Dr. David S. Cooper, Thyroid Unit, containing 1.7 ppm iodide (Purina rodent laboratory chow no. Massachusetts General Hospital, Boston, Massachusetts 02114. 5001) and water containing PTU in varying concentrations. * A preliminary account of parts of this research was presented as Abstract T-5 at the 57th Meeting of the American Thyroid Association, Groups of approximately 50 rats were used for the following Minneapolis, MN, 1981. This work was supported by USPHS Grants studies. AM-16791 and AM-07028. t Recipient of a New Investigator Award from the NIH (1-R23-AM- Exp I. This experiment was designed to assess serum and 28465-01). thyroid PTU levels and PTU effects on thyroid function after 921 922 COOPER ET AL. Endo • 1983 Volll3«No3 1 week of PTU treatment. Groups of seven or eight animals PBI or in serum concentrations of T4, T3, rT3, or TSH. each were given PTU in their drinking water in concentrations Thereafter, significant and progressive decreases in thy- ranging from 0.0001-0.01%, and were autopsied 1 week later. roid PBI and serum T4 and T3 were noted with increasing Exp II. This experiment was similar to Exp I, except that the PTU concentration. Increases in serum TSH into the duration of treatment was 1 month instead of 1 week. range seen after thyroidectomy (Kieffer, J. D., unpub- lished observations) were noted, and a dose-dependent Exp III. This experiment was designed to study PTU disap- elevation of the rT3 to T4 ratio was seen. [Since serum pearance rates and thyroid recovery patterns after short and T4 is the primary source of circulating rT3 (24), the rT3 long term PTU exposure. Animals were maintained on a con- to T ratio was employed to correct rT data for the stant concentration of PTU (0.05%) for either 1 week or 1 4 3 month. The drug was withdrawn, and groups of six or seven decreasing serum T4 concentrations.] rats were autopsied at intervals from 4 h to 14 days after drug The changes in thyroid PBI and serum T4 were plotted discontinuation. against the log PTU concentration in the drinking water, For all experiments, animals were injected with 40-60 /iCi the log PTU serum concentration, and the thyroid PTU 123I 1 h before autopsy. Animals were bled by decapitation content (Fig. 1). Fifty percent suppression of thyroid PBI without anesthesia, and serum was separated by centrifugation. occurred at a PTU concentration of 0.0005% correspond- The thyroid glands were rapidly dissected, weighed, and indi- ing to serum and thyroid PTU concentrations of 0.3 ng/ vidually homogenized in glass homogenizers in 1.5 ml ice-cold ml (1.8 HM) and 300 ng/gland (88 fiM), respectively. Fifty 0.1 M NaCl in 0.05 M Na K phosphate buffer, pH 7.4. The percent suppression of T4 required higher serum and thyroid homogenates were spun at 2300 x g for 45 min, and thyroid PTU levels (~1 txg/va\ and 500 ng/gland, respec- the supernatants were saved for the determination of the intra- tively). Maximal changes in PBI and T4 occurred over a thyroid PTU concentration. Serum and thyroid extracts were less than 10-fold range of thyroid PTU (50-500 ng/ stored at -20 C until assay. gland), but over a 100-fold range of serum PTU (0.05- Determination of thyroid PBI. To determine intrathyroid PBI, 5.0 400 (A 0.1% BSA in 0.05 M phosphate buffer were added to a 100-yu.l aliquot of thyroid homogenate. The protein was precip- Exp II itated by the addition of 500 n\ 10% trichloroacetic acid (TCA). The mixture was spun at 2300 X g for 10 min, and the pellet PTU levels and changes in thyroid function with in- was washed once with 500 (A 5% TCA. Intrathyroid PBI was creasing PTU concentration in the drinking water after calculated as the ratio of TCA-precipitable radioactivity to total 1 month of treatment are shown in Table 2. Compared radioactivity. with the 1 week treatment group, T4 values were lower at each PTU concentration, although the differences Assays. PTU, T4, T3, rT3, and TSH were measured by RIA, as were significant only at PTU concentrations of 0.0005% previously described (18-21). As noted before (18), the PTU RIA that was employed only measured free or unbound PTU and 0.005%. In contrast, thyroid PBI, serum T3 and within the thyroid. Therefore, thyroid PTU refers only to this TSH, and the rT3 to T4 ratio after 1 month of treatment fraction (~75%) of the total thyroid PTU. did not differ significantly from those seen at the same PTU concentrations after 1 week of treatment. Statistical methods. Experimental values were expressed as the Changes in thyroid PBI and serum T4 after 1 month mean ± SE. Molar thyroid PTU concentrations were calculated of treatment were plotted against log PTU concentration from thyroid drug content and thyroid weight (nanograms per in the drinking water, log serum PTU concentration, and g = nanograms per ml). The estimated amount of PTU ingested thyroid PTU content (Fig. 2). The PTU concentration was based on an average water intake of 20 ml/day • rat.
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