Role of TSH in the Changes in Thyroidal Metabolism of [<sup>35</sup>S]Methimazole in Phenobarbital and Thyroxine-Treated Rats

Lees, Jean F. H.; Alexander, W. D.; Lewis, Mridula; Evered, David

doi:10.1210/endo-100-3-765

Cited by 15 publications

(4 citation statements)

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“…This effect is presumably caused by an increase in TSH secretion due to a phenobarbitone-induced increase in the peripheral turnover of thyroxine (Cavalieri et al, 1973;Lees et al, 1977). Phenobarbitone also increases the intrathyroidal oxidation of methimazole, while the intrathyroidal metabolism of propylthiouracil remains unchanged.…”

Section: Drug Interactionsmentioning

confidence: 99%

Clinical Pharmacokinetics of Antithyroid Drugs

Kampmann

Hansen

1981

Clinical Pharmacokinetics

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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.

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Section: Drug Interactionsmentioning

confidence: 99%

Clinical Pharmacokinetics of Antithyroid Drugs

Kampmann

Hansen

1981

Clinical Pharmacokinetics

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“…All samples from an experiment were assayed in a single batch to avoid inter-assay variation. Assays of TSH (Lees, Alexander, Lewis «fe Evered, 1977), total T3 (Hesch «fe Evered, 1973) and free T3 (Yeo, Lewis & Evered, 1977) were carried out as previously described with the substitution of incubation medium for serum in the 'standard' and 'unknown' tubes.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Thyrotrophin-Releasing Hormone Responsiveness by Physiological Concentrations of Thyroid Hormones in the Cultured Rat Pituitary Gland

Mj¹,

Yeo²,

Green³

et al. 1977

Journal of Endocrinology

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Diced quarter anterior pituitaries from mature females Wistar rats were cultured in synthetic medium with or without added serum. Using each culture as its own control, the thyrotrophin-releasing hormone (TRH) dose-thyrotrophin (TSH) response characteristics of both media were similar; significant TSH secretion being stimulated at TRH doses around 1-5 X 10(-9) mol/l. During days 1-3 of culture, basal TSH secretion fell significantly but TRH responsiveness was unchanged. Neither tri-iodothyronine (T3) nor thyroxine (T4) influenced basal TSH secretion. In both culture media inhibition of TRH responsiveness was demonstrated with concentrations of T3 and T4 within the ranges 1-5 X 10(-12) to 1-5 X 10(-9) mol/l for T3 and 6-5 X 10(-10) to 6-5 X 10(-7) mol/l for T4. Equivalent inhibition was accompanied by similar T3 concentrations whether T3 or T4 supplements were used, suggesting that T4 itself has no feedback action. The similar concentrations of T3 required to inhibit TRH responsiveness in media either with or without serum suggest that the pituitary is responsive not only to free but also to total thyroid hormone concentrations, since serum-free medium contains no thyroid hormone-binding protein.

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“…produced an increased clearance of thyroxine in the liver of female rats (21). One common mechanism by which a number of structurally diverse agents appear to produce such an effect in rodents is via increased hepatic thyroxine catabolism (22)(23)(24)(25). The increased clearance of thyroxine can occur secondary to activation or induction of thyroxine-specific UDP-glucuronosyltransferase as shown for phenobarbital and clofibrate (8,26).…”

Section: Activities Of Liver Drug-metabolizing Enzymesmentioning

confidence: 99%

Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

Ohtawa¹,

Masuda²,

Karasawa³

et al. 1995

European Journal of Drug Metabolism and Pharmacokinetics

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Fluvastatin (FV), a new cholesterol-lowering agent, has been studied for its effects on hepatic microsomal drug-metabolizing enzymes in male rats. FV was orally administered in dosages of 1, 5, and 30 mg/kg/day for 7 consecutive days. 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activities were markedly decreased at all dose levels. The amount of microsomal protein and the contents of cytochromes P450 and b5 did not change. No induction of aniline hydroxylase, aminopyrine N-demethylase, testosterone hydroxylases (15 alpha-, 7 alpha-, 6 beta-, 16 alpha-, and 16 beta-), and UDP-glucuronosyltransferase were found. On the other hand, 7-ethoxycoumarin o-deethylase activity was slightly increased and lauric acid omega-1-hydroxylase activity tended to be decreased after treatment with FV.

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Role of TSH in the Changes in Thyroidal Metabolism of [³⁵S]Methimazole in Phenobarbital and Thyroxine-Treated Rats

Cited by 15 publications

References 0 publications

Clinical Pharmacokinetics of Antithyroid Drugs

Clinical Pharmacokinetics of Antithyroid Drugs

Inhibition of Thyrotrophin-Releasing Hormone Responsiveness by Physiological Concentrations of Thyroid Hormones in the Cultured Rat Pituitary Gland

Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

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Role of TSH in the Changes in Thyroidal Metabolism of [35S]Methimazole in Phenobarbital and Thyroxine-Treated Rats

Cited by 15 publications

References 0 publications

Clinical Pharmacokinetics of Antithyroid Drugs

Clinical Pharmacokinetics of Antithyroid Drugs

Inhibition of Thyrotrophin-Releasing Hormone Responsiveness by Physiological Concentrations of Thyroid Hormones in the Cultured Rat Pituitary Gland

Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

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Role of TSH in the Changes in Thyroidal Metabolism of [³⁵S]Methimazole in Phenobarbital and Thyroxine-Treated Rats