THE EFFECT OF PROPYLTHIOURACIL ON THE CONVERSION OF MONOIODOTYROSINE TO DIIODOTYROSINE<sup>1</sup>

Slingerland, D. Ward; Graham, Dorothy E.; Josephs, Roma K.; Mulvey, Philip F.; Trakas, Anne P.; Yamazaki, Eiichi

doi:10.1210/endo-65-2-178

Cited by 43 publications

(14 citation statements)

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“…In addition, there is evidence that even 1 week of PTU treatment results in intrathyroid iodine deficiency (10), which also favors thyroid production of T 3 over T 4 (32). Finally, a direct effect of PTU (in small doses) to cause preferential synthesis of T 3 over T 4 has been described (2,33).…”

Section: Discussionmentioning

confidence: 99%

“…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. {Endocrinology 113: 921,1983) T HE in vivo pharmacology of the antithyroid drug propylthiouracil (PTU) in the rat has been studied by a large number of investigators (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Most pharmacokinetic studies, however, have involved either single injections of radiolabeled PTU or short treatment courses (<1 week) with unlabeled PTU.…”

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confidence: 99%

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

et al. 1983

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 1983

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“…Propylthiouracil prevents binding of iodine in the thyroid beyond the level of monoiodotyrosine and the extent of blockade is dose dependent. 19 In the current study, absolute prevention of organic binding of iodine was not attained during administration of propylthiouracil but considerable inhibition was achieved early in the study as indicated by subnormal levels of serum PBI and reduced thyroidal affinity for 1311. The considerably greater increase in size of the thyroid in females may account for the more normal levels of serum PBI in this sex.…”

Section: Discussionmentioning

confidence: 48%

Cancer of the thyroid, goitrogenesis and thyroid function in syrian (golden) hamsters

Sichuk¹,

Money²,

Der³

et al. 1968

Cancer

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Goitrogenesis and an increased frequency of cancer of the thyroid was induced by an iodine‐deficient rice diet or propylthiouracil. Goitrogenesis but not the occurrence of cancer of the thyroid was inhibited by supplementation of the rice diet with potassium iodide. Female hamsters were much more susceptible to goitrogenesis but not to cancer of the thyroid. Measures of thyroid function gave similar results in both sexes. Hamsters on the rice diet had normal serum PBI levels, markedly enhanced thyroidal affinity for 131I and subnormal or non‐detectable levels of serum inorganic‐iodide (I). Animals given propylthiouracil had subnormal levels of PBI, inconsistently subnormal thyroidal affinity for 131I and normal serum I. Serum calcium levels were subnormal in hamsters fed rice for 9 months or longer. The TSH‐dependent characteristics of thyroid tissue appear necessary for thyroid cancerogenesis but the relationship between marked hyperplasia, due to chronically high TSH levels, and the frequency of cancer of the thyroid is obscure for several reasons.

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“…Although Williams and Doniach (1961) showed that single doses of phenindione prevented the organic binding of iodine by the rat thyroid, the minimum dose required was of the order of 4 mg., equivalent on a weight for weight basis to a human dose of about 1200 mg. Drugs of the thionamide group, which includes propylthiouracil, are more potent inhibitors of two later stages in iodothyronine biosynthesis, the coupling of two iodotyrosine molecules to form iodothyronine and the formation of diiodotyrosine, than of the initial iodination of tyrosine to form monoiodotyrosine (Slingerland et al, 1959;Richards & Ingbar, 1959). Thus these drugs in doses which fail to block the organic binding of iodine may still significantly inhibit thyroxine synthesis, and this might be the effect of phenindione.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Long-Term Phenindione Treatment on Thyroid Function

Stewart

Grayson

1966

Scott Med J

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THE EFFECT OF PROPYLTHIOURACIL ON THE CONVERSION OF MONOIODOTYROSINE TO DIIODOTYROSINE¹

Cited by 43 publications

References 0 publications

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

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

Cancer of the thyroid, goitrogenesis and thyroid function in syrian (golden) hamsters

The Effect of Long-Term Phenindione Treatment on Thyroid Function

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THE EFFECT OF PROPYLTHIOURACIL ON THE CONVERSION OF MONOIODOTYROSINE TO DIIODOTYROSINE1

Cited by 43 publications

References 0 publications

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

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

Cancer of the thyroid, goitrogenesis and thyroid function in syrian (golden) hamsters

The Effect of Long-Term Phenindione Treatment on Thyroid Function

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THE EFFECT OF PROPYLTHIOURACIL ON THE CONVERSION OF MONOIODOTYROSINE TO DIIODOTYROSINE¹