Concentration of 35S-propylthiouracil by the thyroid gland and its relationship to anion trapping mechanism

Marchant, B.; Alexander, W. D.; Robertson, James Louis; Lazarus, John H.

doi:10.1016/0026-0495(71)90021-7

Cited by 53 publications

(23 citation statements)

References 8 publications

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“…In our model, we included the irreversible formation of inactive PTU in addition to a slow elimination of the inactive form. As shown in Figure 5,13, 44, 45 this results in a very good description of the observed thyroid tissue concentration data.…”

Section: Resultssupporting

confidence: 68%

“…The surface area was estimated to be 20.63 cm 2 (95% confidence interval ranging from 4.24–37.13 cm 2 ). Figure 5 13, 44, 45 shows that our model simulations correspond well with the experimental thyroid tissue concentration data for omadacycline, amiodarone, and DEA.…”

Section: Resultssupporting

confidence: 66%

“…The simulated tissue concentration corresponds to the volume‐weighted sum of the interstitial, intracellular, and luminal concentrations. Circles represent individual or mean ± SD of observed data extracted from literature 13, 44, 45. For omadacycline, diamonds represent the concentration of total radioactivity (as omadacycline does not undergo metabolism, the total radioactivity is assumed to reflect the concentration of the parent drug).…”

Section: Resultsmentioning

confidence: 99%

“…This is supported by the similar levels of plasma measurements based on concentration data and total radioactivity (compare Figure 5). 13, 44, 45 …”

Section: Resultsmentioning

confidence: 99%

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Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Pilari

Gaub

Block

et al. 2017

CPT Pharmacometrics Syst. Pharmacol.

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We extended a generic whole‐body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK‐Sim and MoBi. The capability of the PBPK approach to simulate the testes and thyroid tissue concentration data was demonstrated using a series of test compounds. The presented organ model structures and parameterization yielded a close agreement between observed and simulated tissue concentrations over time. The organ models are ready to be used to predict the pharmacokinetics of passively entering drugs in the testes and thyroid tissue in a generic PBPK modeling framework.

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Section: Resultssupporting

confidence: 68%

Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

“…This is supported by the similar levels of plasma measurements based on concentration data and total radioactivity (compare Figure 5). 13, 44, 45 …”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Pilari

Gaub

Block

et al. 2017

CPT Pharmacometrics Syst. Pharmacol.

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show abstract

“…This may be sufficient to continually divert [E-I] toward drug oxidation, thus inhibiting iodination. Data reported from Alexander's laboratory (21) possibility that intrathyroidal drug metabolism may be blocked in rats receiving large, repeated doses of PTU and MMI.…”

Section: ) [E-i] + Tyrosyl -» Iodotyrosine + Ementioning

confidence: 92%

The Mechanism of Action of the Thioureylene Antithyroid Drugs

Taurog

1976

Endocrinology

242

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A model incubation system containing purified thyroid peroxidase (TPO) was used to study the mechanism of action of the thioureylene anti-thyroid drugs--propylthiouracil (PTU), methylmercapto imidazole (MMI) and carbimazole. Two general types of experiments were performed: a) measurement of the inhibitory effects of the drugs on TPO-catalyzed iodination and on TPO-catalyzed oxidation of guaiacol, and b) studies of the metabolism of PTU and MMI by the TPO model system. The major observations can be summarized as follows: 1) The thioureylene drugs are potent inhibitors of TPO-catalyzed iodination of protein and tyrosine. Their potency increases greatly as the concentration of I- decreases. 2) The thioureylene drugs are also potent inhibitors of TPO-catalyzed oxidation of guaiacol, a reaction that does not involve iodide. 3) MMI and PTU are readily oxidized in the model incubation system when iodide is present but not in the absence of iodide. The rate of oxidation increased as the iodide concentration was increased from 10 to 100 muM. 4) Oxidation of PTU and MMI by the model incubation system is inhibited by relatively slight increases in the concentration of PTU and MMI. These drugs are capable of inhibiting their own and each other's metabolism. 5) Inhibition of iodination is competitively antagonized by iodide at low drug concentrations, but not at higher drug concentrations. 6) Inhibition of iodination by MMI and PTU may be either reversible (low ratio of drug to iodide), or irreversible (higher ratio of drug to iodide). In reversible inhibition the iodination is inhibited for a period which may be as brief as 2 min or as long as 20 min, but thereafter, iodination begins, and there is escape from inhibition. During the lag-period there is extensive metabolism of the drug. In the case of irreversible inhibition of iodination is inhibited completely or almost completely for 60 min, and drug oxidation during this period is relatively low. 7) Irreversible inhibition may be transformed into reversible inhibition by increasing the concentration of TPO or the concentration of iodide. However, increasing the concentration of H2O2 or of tyrosine does not overcome irreversible inhibition. On the basis of these findings and of current views concerning the mechanism of enzymatic iodination, a scheme is proposed for the mechanism of inhibition by thioureylene drugs of TPO-catalyzed iodination of protein and tyrosine.

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Prospective Randomized Comparison of Propylthiouracil

Gwinup¹

1978

JAMA

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Concentration of 35S-propylthiouracil by the thyroid gland and its relationship to anion trapping mechanism

Cited by 53 publications

References 8 publications

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

The Mechanism of Action of the Thioureylene Antithyroid Drugs

Prospective Randomized Comparison of Propylthiouracil

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