In U-937 cells, propylthiouracil (5.5-330 μg/mL; 24 h) causes cytotoxicity and growth retardation in a dose-dependent manner [2].

Propylthouracil induces hypothyroidism in C57BL/6J mice and wild WSB/EiJ elk by administering an iodine-deficient diet supplemented with 0.15% Propylthouracil [1].

Cell Viability Assay[2]
Cell Types: U-937 cells
Tested Concentrations: 5.5 μg/mL, 11 μg/mL, 110 μg/mL, 220 μg/mL, 330 μg/mL
Incubation Duration: 24 hrs (hours)
Experimental Results: Dose-dependent way to induce cytotoxicity.

Animal/Disease Models: Adult C57BL/6J and wild-type WSB/EiJ male mice (8 weeks old) [1]
Doses: 1.5 g/kg Dietary
Route of Administration: Iodine-deficient diet; continued for 7 weeks
Experimental Results: In adult C57BL/6J and wild-type WSB/EiJ induces hypothyroidism in male mice.

Absorption, Distribution and Excretion
Propylthiouracil is well absorbed after oral administration. It is readily absorbed and extensively metabolized. Approximately 35% of the drug is excreted unchanged and in conjugated forms in the urine within 24 hours. Elimination: Less than 1% of the drug is excreted unchanged in the urine. Systemic clearance is approximately 7 liters/hour. Dialysis: Hemodialysis has no significant effect on elimination and pharmacokinetics. In one patient undergoing hemodialysis, 5% of a 200 mg oral dose was cleared after 3 hours of hemodialysis; the elimination rate was not significantly altered. Peak serum concentrations decreased (from 7.9 μg/mL to 4.9 μg/mL), but remained within the general therapeutic range. Although the distribution of propylthiouracil in human tissues and fluids is not fully understood, the drug appears to concentrate in the thyroid gland. Propylthiouracil readily crosses the placenta. Propylthiouracil is distributed into breast milk; however, some studies suggest that only about 0.007-0.077% of a single dose is distributed. Following oral administration of 200-400 mg of propylthiouracil, it is rapidly and readily absorbed from the gastrointestinal tract, with peak plasma concentrations of approximately 6-9 μg/mL within 1-1.5 hours after a single dose. In one study, the drug was administered both orally and intravenously, and approximately 75% of the oral dose was absorbed. Plasma concentrations appear to be independent of therapeutic efficacy. Time to peak effect: With a daily dose of 300 mg, it takes an average of 17 weeks for serum T3 and T4 concentrations to return to normal. For more complete data on the absorption, distribution, and excretion of propylthiouracil (19 in total), please visit the HSDB records page.

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Metabolism/Metabolites
Propylthiouracil is concentrated in the thyroid gland. Four sulfur-35 compounds were detected in rats and humans by thin-layer chromatography: unmetabolized propylthiouracil, (35)-sulfate, an unknown propylthiouracil metabolite, and protein-bound sulfur-35…
Biotransformation: Primarily by glucuronidation. Approximately 33% of the oral dose is metabolized via the first-pass effect.
Because propylthiouracil contains four functional groups, each of which can bind to glucuronic acid, it is expected that there will be more than one propylthiouracil glucuronide conjugate.
Although the exact metabolic pathway of propylthiouracil is not fully understood, the drug is rapidly metabolized to glucuronide conjugates and other minor metabolites, requiring frequent dosing to maintain its antithyroid effect. The drug and its metabolites are excreted in the urine, with approximately 35% of the dose excreted within 24 hours. For more complete metabolite/metabolite data on propylthiouracil (8 metabolites), please visit the HSDB record page. Elimination pathway: Propylthiouracil is readily absorbed and extensively metabolized. Approximately 35% of the drug is excreted in the urine in its intact and conjugated form within 24 hours. Half-life: 2 hours

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Biological half-life
2 hours
The elimination half-life of propylthiouracil is reported to be approximately 1–2 hours.
The plasma half-life of propylthiouracil is 1 to 2 hours.
After gastrointestinal absorption, the plasma half-lives are reported to be 2.5 hours (human) and 4.8 hours (rat).
The plasma half-life of propylthiouracil is approximately 75 minutes.
After oral administration of propylthiouracil tablets, absorption in humans is rapid, reaching peak plasma concentrations within 60–120 minutes; the biological half-life in subjects with normal thyroid function is approximately 60 minutes.

Toxicity Summary
Propylthiouracil binds to thyroid peroxidase, thereby inhibiting the conversion of iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (with hydrogen peroxide as a cofactor) and catalyzes the incorporation of the resulting iodine molecule into the 3- and/or 5-position of the tyrosine phenolic ring in thyroglobulin. Thyroglobulin degrades to produce thyroxine (T4) and triiodothyronine (T3), which are the main hormones produced by the thyroid gland. Therefore, propylthiouracil effectively inhibits the synthesis of thyroid hormones. Toxicity Data
Oral administration, rats: LD50 = 1250 mg/kg. Interactions In addition to inhibiting hormone synthesis, propylthiouracil also inhibits the peripheral deiodination of thyroxine to triiodothyronine. Methimazole does not have this effect and can antagonize the inhibitory effect of propylthiouracil. We investigated the effects of dl-α-tocopherol (vitamin E) on 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism in rats using immunohistochemistry. The experimental animals were divided into four groups. Group 1 served as the control group; Group 2 rats were injected with propylthiouracil (PTU, 10 mg/kg) for 15 consecutive days; Group 3 rats were injected with PTU plus vitamin E (10 mg/100 g) for 15 consecutive days; and Group 4 rats were injected with PTU for 15 consecutive days, followed by 15 days of continued feeding after drug withdrawal. At the end of the experiment, the animals were sacrificed, blood samples were collected, and thyroid tissue was harvested for immunohistochemical staining and quantitative analysis to detect the expression of PCNA (a cell proliferation marker), Bax (a pro-apoptotic marker), and Bcl-2 (an anti-apoptotic marker). The results showed that, compared with the other groups, the number of PCNA-immunopositive cells in the follicular epithelial cells of Group 2 rats was significantly increased (p<0.05). Following vitamin E treatment, the number of PCNA-positive cells decreased (p<0.05), while the number of Bax-positive cells increased (p<0.05). The number of Bcl-2-positive follicular epithelial cells in group IV rats was higher than in other groups (p<0.05). These results suggest that hypothyroidism can induce thyroid cell proliferation, while vitamin E may promote thyroid degeneration. Female Sprague-Dawley rats aged 50-60 days were administered 7,12-dimethylbenzo[a]anthracene (DMBA) dissolved in sesame oil via gavage at doses of 6.5, 10, 13.5, or 15 mg/rat. Propylthiouracil was added to drinking water at concentrations ranging from 0.5 to 4.0 mg/100 mL before and after DMBA treatment (from 17 days before DMBA treatment to the end of the study, a total of 4 months). Administering higher doses of propylthiouracil from 7 days prior to DMBA treatment until the end of the study resulted in severe hypothyroidism, reducing the incidence of mammary tumors in DMBA-treated rats from 68/108 to 3/45 in rats treated with DMBA combined with propylthiouracil. Twenty-one 6-week-old male inbred Wistar rats were fed a basal diet containing 0.15% propylthiouracil (purity not specified). One group was fed alone, while the other group received a single intraperitoneal injection of N-nitrosobis(2-hydroxypropyl)amine (NBHPA) at 2.8 g/kg body weight at the start of the study. The other two groups received either the initial dose of NBHPA or the basal diet (control group). The animals were housed for 20 weeks with a 100% survival rate. Thyroid follicular cell tumors were developed in all 21 rats treated with NBHPA in combination with propylthiouracil, and in 4 of the 21 rats treated with NBHPA alone (p<0.05). No thyroid follicular cell tumors were developed in any of the 21 rats treated with propylthiouracil alone or without any treatment. Among the rats treated with NBHPA in combination with propylthiouracil, 7 developed thyroid tumors, of which 7 developed thyroid cancer. For more complete data on interactions of propylthiouracil (7 in total), please visit the HSDB record page. Non-human toxicity values: Oral LD50 in rats: 1980 mg/kg

[1]. A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation. Int J Mol Sci. 2022 Oct 8;23(19):11938.

[2]. Synergistic effect of phospholipid-based liposomes and propylthiouracil on U-937 cell growth. J Liposome Res. 2005;15(3-4):215-27.

Therapeutic Uses
MeSH Title: Antimetabolites, Antithyroid Drugs …Propylthiouracil is indicated for the treatment of hyperthyroidism, including preoperative or pre-radiotherapy, and as adjunctive therapy for thyrotoxicosis or thyroid storm. Because propylthiouracil inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3), it may be superior to methimazole in the treatment of thyroid storm. Experimental Applications: Propylthiouracil has been shown to reverse histological changes in rat alcoholic hepatitis and is considered a potential treatment for this disease in humans. Experimental Applications: Pretreatment with propylthiouracil for 12 days prevented acetaminophen-induced increases in transaminase activity. Increased levels of reduced glutathione in the liver and suppression of inflammatory responses in necrotic liver tissue appear to be mechanisms by which hypothyroidism is protected. For more complete data on the therapeutic uses of propylthiouracil (14 in total), please visit the HSDB record page.
Drug Warnings
Although reported infrequently, some patients receiving propylthiouracil have reported serious adverse reactions, including suppression of myeloid hematopoiesis leading to agranulocytosis, granulocytopenia, and thrombocytopenia; aplastic anemia; drug fever; lupus-like syndrome (including splenomegaly); severe liver reactions (including encephalopathy, fulminant hepatic necrosis, and death); periarteritis; and hypoprothrombinemia and bleeding. In addition, nephritis and interstitial pneumonia have been reported. Cutaneous vasculitis may present as purpura and/or bullous hemorrhagic lesions or erythema nodosum, which may progress to necrotizing ulcers; polymyositis may also occur.
The most serious side effect of propylthiouracil is likely agranulocytosis, most cases appear to occur within the first 2 months of treatment, but in rare cases it may occur after 4 months of treatment. Compared to younger patients, patients over 40 years of age appear to have a significantly increased risk of propylthiouracil-induced agranulocytosis, but unlike methimazole, a dose-related association has not been established. Although the mechanism by which propylthiouracil induces agranulocytosis is unclear, antigranulocyte antibodies have been reported in some patients with thioamide-induced agranulocytosis; the direct bone marrow toxicity of these drugs has not been ruled out and may also be a contributing factor to hyperthyroidism. Propylthiouracil can cross the placenta, and its use by pregnant women may harm the fetus; the drug can induce goiter and hypothyroidism (cretinism) in developing fetuses. If this drug is used to treat hyperthyroidism during pregnancy, the manufacturer advises that the dosage must be carefully adjusted, using an adequate but not excessive dose of propylthiouracil. The manufacturer notes that because thyroid dysfunction in many women improves as pregnancy progresses, the dosage can be reduced, and in some patients, propylthiouracil can be discontinued 2 to 3 weeks before delivery. If propylthiouracil is used during pregnancy, or if a woman becomes pregnant while taking this medication, she should be informed of the potential risks to the fetus. ...Controversy surrounding the treatment of thyrotoxicosis during pregnancy. Antithyroid drugs can cross the placenta and may cause fetal hypothyroidism and goiter. ...Currently, three treatment options are available, each with its supporters: minimum dose antithyroid drugs, full dose antithyroid drugs combined with thyroid hormone replacement therapy, or surgical treatment. /Antithyroid Drugs/
For more complete data on propylthiouracil (20 in total), please visit the HSDB records page.

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Pharmacodynamics
Propylthiouracil is a thionamide antithyroid drug. Graves' disease is the most common cause of hyperthyroidism. This is an autoimmune disease in which the patient's own antibodies attach to thyroid-stimulating hormone receptors within thyroid cells, triggering excessive secretion of thyroid hormones. The two thyroid hormones produced by the thyroid gland, thyroxine (T4) and triiodothyronine (T3), are formed by the binding of iodine and a protein called thyroglobulin with the help of peroxidase. Propylthiouracil (PTU) reduces thyroid hormone production by inhibiting the normal interaction between iodine and peroxidase with thyroglobulin, preventing the production of T4 and T3. PTU also interferes with the conversion of T4 to T3; since T3 has higher activity than T4, it also reduces the activity of thyroid hormones. The action and usage of propylthiouracil are similar to those of methimazole.

C7H5D5N2OS

175.26

170.051

51-52-5

Propylthiouracil-d5;1189423-94-6

657298

White to off-white solid powder

1.2±0.1 g/cm3

355.2±34.0 °C at 760 mmHg

218-220 °C(lit.)

168.6±25.7 °C

0.0±0.8 mmHg at 25°C

1.601

-0.32

2

2

2

11

223

0

KNAHARQHSZJURB-UHFFFAOYSA-N

InChI=1S/C7H10N2OS/c1-2-3-5-4-6(10)9-7(11)8-5/h4H,2-3H2,1H3,(H2,8,9,10,11)

6-propyl-2-sulfanylidene-1H-pyrimidin-4-one

Procasil-d5; Propylthiouracil-d5; Propylthiouracil

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~587.44 mM)
H2O : ~0.67 mg/mL (~3.94 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (14.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (14.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (14.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)