Propylthiouracil

170.23

170.23

200-103-2

721M9407IY

757302|70461|6498

DTXSID5021209

C781

White crystalline powder of starch-like appearance to eye and to touch

H03BA02|H - Systemic hormonal preparations, excl. sex hormones and insulins

29335995

73.2

0.8

6-n-propyl-2-thiouracil appears as odorless white crystalline powder of starch-like appearance. Bitter taste. Saturated solution is neutral or slightly acid to litmus. (NTP, 1992)

1.2±0.1 g/cm3

219-221 °C

355.2ºC at 760mmHg

300 °C

1.601

H2O: 1.1 g/L

Refrigerator

6.9X10-8 mm Hg at 25 deg C (est)

LD50 orally in Rabbit: 1250 mg/kg

Bitter

Saturated aq soln is neutral or slightly acid to litmus

Henry's Law constant = 1.1X10-9 atm-cu m/mol at 25 °C (est)

134.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Sensitive to light|Hydroxyl radical reaction rate constant = 8.9X10-11 cu cm/molec-sec at 25 °C (est)

Sensitive to light. May be sensitive to prolonged exposure to air. Insoluble in water.

Amides and Imides

6-N-PROPYL-2-THIOURACIL is incompatible with strong oxidizing agents, strong acids and strong bases. Forms complexes with divalent metals. Reacts with sulfhydryl-oxidizing agents (NTP, 1992). When reduced will produce hydrogen sulfide.

NONH for all modes of transport

3

22-40

36/37-45

YR1400000

Xn,Xi

Harmful/Irritant

Stable. Combustible. Incompatible with strong oxidizing agents, strong acids, strong bases. Light sensitive.

P281

H302-H351

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations. SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.|PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/|For more Disposal Methods (Complete) data for PROPYL THIOURACIL (6 total), please visit the HSDB record page.

Forms complexes with metals and reacts with sulfhydryl-oxidizing agents

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Propyl Thiouracil (51-52-5) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s156prop.pdf]

Flash point data for this chemical are not available; however it is probably combustible. (NTP, 1992)

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 47 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Danger|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P312, P308+P313, P314, P330, P405, and P501

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, dampen the solid spill material with 5% ammonium hydroxide, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% ammonium hydroxide to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% ammonium hydroxide followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store under refrigerated temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)|PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/|For more Preventive Measures (Complete) data for PROPYL THIOURACIL (9 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

Oral, rat: LD50 = 1250 mg/kg.

Propylthiouracil has been associated with transient, asymptomatic elevations in serum aminotransferase levels, typically during the first 3 months of therapy. These elevations are rarely clinically significant and usually resolve even with continuation of therapy. Propylthiouracil is also capable of causing clinically apparent, idiosyncratic liver injury at a rate estimated to be at least 1 per 1000 persons exposed. The onset of hepatotoxicity is usually within 2 to 12 weeks of starting, and the pattern of enzyme elevations is typically hepatocellular, although cholestatic and mixed patterns have also been described (Cases 1 to 3). In some cases, onset is months or more than a year after initiating therapy, sometimes shortly after dose modification. Rash, fever and eosinophilia are not uncommon, but are rarely prominent or severe. Some cases of propylthiouracil hepatotoxicity present with autoimmune features including antinuclear antibody and hyperglobulinemia, perhaps because of the background of autoimmune thyroid disease. While most patients start to improve with stopping therapy, many cases are severe and some have been associated with acute liver failure with death or need for emergency liver transplantation (Case 4). Liver injury from propylthiouracil appears to be more common and perhaps more severe in children and adolescents than in adults. Rates of acute liver failure due to propylthiouracil are estimated to be 1:10,000 in adults and as high as 1:2000 in children.

In addition to blocking hormone synthesis, propylthiouracil inhibits the peripheral deiodination of thyroxine to triiodothyronine. Methimazole dose not have this effect and can antagonize the inhibitory effect of propylthiouracil.|We have investigated immunohistochemically the effect of dl-alpha-tocopherol (vitamin E) on thyroid gland with 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism in rats. The animals were divided into four groups. Rats in group I were designated as control, rats in group II were treated with injections of PTU (10 mg/kg) for 15 days, rats in group III were treated with injections of PTU+vitamin E (10 mg/100 g) for 15 days. Rats in group IV were treated with injections PTU for 15 days and kept for 15 next days after cessation of PTU treatment. At the end of experiment, the animals were killed by decapitation, blood samples were obtained, thyroid tissues were collected and processed for quantitative evaluation of immunohistochemical PCNA (marker of cell proliferation), Bax (pro-apoptotic marker) and Bcl-2 (anti-apoptotic marker) staining. There was an increase in the number of PCNA-immunopositive cells in follicular epithelial cells of group II rats compared with other groups (p<0.05). After vitamin E treatment, the number of PCNA-immunopositive cells decreased (p<0.05) while the number of Bax-immunopositive cells increased (p<0.05). The number of Bcl-2-positive follicular epithelial cells of group IV rats was higher than in those of other groups (p<0.05). The results of this study indicate that hypothyroidism induces cell proliferation in the thyroid gland and vitamin E may promote involution of the gland.|Female Sprague-Dawley rats, 50-60 days of age, were given 7,12-dimethylbenz[ a]anthracene (DMBA) in sesame oil by oral gavage at a dose of 6.5, 10, 13.5 or 15 mg per animal. Propylthiouracil was given in the drinking-water at concentrations between 0.5 and 4.0 mg/100 mL for various times before and after the DMBA treatment, ranging from 17 days before DMBA up to the end of the study at 4 months. Severe hypothyroidism produced by administration of propylthiouracil at the higher dose from 7 days before DMBA up to study termination reduced the mammary tumor incidence from 68/108 in rats given DMBA only to 3/45 in those given DMBA plus propylthiouracil.|Two groups of 21 male inbred Wistar rats, 6 weeks of age, were fed basal diet containing propylthiouracil [purity not specified] at a concentration of 0.15% either alone or in combination with a single intraperitoneal injection of N-nitrosobis(2- hydroxypropyl)amine (NBHPA) at the start of the study at a dose of 2.8 g/kg bw. Two additional groups received the initiating dose of NBHPA alone or basal diet alone (control group). The animals were maintained for 20 weeks, at which time the survival rate was 100%. Thyroid follicular-cell tumors occurred in 21/21 rats given NBHPA plus propylthiouracil, 4/21 given NBHPA only (p<0.05) and 0/21 given propylthiouracil only or no treatment. Of the rats given NBHPA plus propylthiouracil, seven of those bearing thyroid tumors had thyroid carcinomas.|For more Interactions (Complete) data for PROPYL THIOURACIL (7 total), please visit the HSDB record page.

LD50 Rat oral 1980 mg/kg

Thyrotoxicosis occurs in about 0.2% of pregnancies and is caused most frequently by Graves' disease. Antithyroid drugs are the treatment of choice ... As pregnancy progresses, Graves' disease often improves. Indeed, it is not uncommon for patients either to be on very low doses or off all antithyroid drugs completely by the end of pregnancy. Therefore, the antithyroid drug dose should be reduced, and maternal thyroid function should be frequently monitored in order to decrease chances of fetal hypothyroidism. Relapse or worsening of Graves' disease is common after delivery, and patients should be monitored closely. Propylthiouracil is the drug of choice in nursing women, since very small amt of the drug appear in breast milk and do not appear to affect thyroid function in the suckling baby.

82%

Propyl thiouracil's production and use as thyroid inhibitor(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 23(SRC), determined from a structure estimation method(2), indicates that propyl thiouracil is expected to have very high mobility in soil(SRC). Volatilization of propyl thiouracil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.1X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Propyl thiouracil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-8 mm Hg(SRC), determined from a fragment constant method(4). Propyl thiouracil was not degraded in a screening study using an activated sludge inoculum over a 4 week incubation period(5), suggesting biodegradation in soil will be slow.|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 23(SRC), determined from a structure estimation method(2), indicates that propyl thiouracil is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.1X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), BCF values of <2 to <4 measured in fish(6), suggest bioconcentration in aquatic organisms is low(SRC). Propyl thiouracil was not degraded in a screening study using an activated sludge inoculum over a 4 week incubation period(6) suggesting biodegradation in water will be slow. The potential for direct photolysis in sunlit surface water exists since propyl thiouracil absorbs light greater than 290 nm(7); however, no rates for this potential reaction were located(SRC,2006).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), propyl thiouracil, which has an estimated vapor pressure of 6.9X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase propyl thiouracil may be removed from the air by wet and dry deposition(SRC). Propyl thiouracil absorbs light >290 nm and may be susceptible to direct photolysis in air(3).

Propyl thiouracil is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1); however, the potential for direct photolysis exists since propyl thiouracil absorbs light greater than 290 nm(2).

A range of BCF values of <2 to <4 were measured for propyl thiouracil at 0.2 mg/L using carp over a 28 day exposure period(1). According to a classification scheme(2), these BCF values suggest bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for propyl thiouracil can be estimated to be 23(SRC). According to a classification scheme(2), this estimated Koc value suggests that propyl thiouracil is expected to have very high mobility in soil(SRC).

The Henry's Law constant for propyl thiouracil is estimated as 1.1X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that propyl thiouracil is expected to be essentially nonvolatile from water surfaces(2). Propyl thiouracil's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected(SRC). Propyl thiouracil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-8 mm Hg(SRC), determined from a fragment constant method(3).

Propylthiouracil is distributed into milk; however, some studies indicate that the extent of distribution is only about 0.007-0.077% of a single dose.|Propylthiouracil (PTU) concentration measured in blood and milk from 9 lactating women after oral administration of 400 mg. Apparently, PTU is not concentrated in human breast milk and recommended dosages to mother result in minimal and presumably clinically insignificant doses to suckling infant.|Propylthiouracil is the drug of choice in nursing women, since very small amt of the drug appear in breast milk and do not appear to affect thyroid function in the suckling baby.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,331 workers (1,661 of these are female) are potentially exposed to propyl thiouracil in the US(1). Occupational exposure to propyl thiouracil may occur through inhalation of dusts or dermal contact with this compound at workplaces where it is produced or used(SRC). The general population may be exposed to propyl thiouracil through its use in the treatment of hyperthyroidism(SRC).

Used to manage hyperthyroidism which is due to an overactive thyroid gland (Grave's disease).

Propylthiouracil is an antithyroid medication used in the therapy of hyperthyroidism and Graves disease. Propylthiouracil has been linked to serum aminotransferase elevations during therapy as well as to a clinically apparent, idiosyncratic liver injury that can be severe and even fatal.

Antithyroid Agents

Mesh Heading: Antimetabolites, Antithyroid Agents|... Propylthiouracil /is/ indicated in the treatment of hyperthyroidism, including prior to surgery or radiotherapy, and as adjuncts in the treatment of thyrotoxicosis or thyroid storm. Propylthiouracil may be preferred over methimazole for use in thyroid storm, since propylthiouracil inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3).|EXPTL USE: Paradoxically propylthiouracil has been shown to reverse histological changes of alcoholic hepatitis in rat and has been proposed as possible treatment for this condition in man.|EXPTL USE: Twelve-day pretreatment with PTU prevented the tylenol-induced increase in transaminase activities. Increase in hepatic reduced glutathione levels and prevention of inflammatory response to necrotic liver tissue appeared to be mechanism in protective action of hypothyroidism.|For more Therapeutic Uses (Complete) data for PROPYL THIOURACIL (14 total), please visit the HSDB record page.

Although reported much less frequently, severe adverse effects, including inhibition of myelopoiesis with resultant agranulocytosis, granulocytopenia, and thrombocytopenia; aplastic anemia; drug fever; lupus-like syndrome (including splenomegaly); severe hepatic reactions (including encephalopathy, fulminant hepatic necrosis, and death); periarteritis; and hypoprothrombinemia and bleeding, have been reported to occur in some patients receiving propylthiouracil. Nephritis and interstitial pneumonitis have also been reported. Cutaneous vasculitis, which may manifest as purpuric and/or bullous hemorrhagic lesions or erythema nodosum, and possibly may progress to necrotic ulcerations, and polymyositis also have occurred.|Agranulocytosis is potentially the most serious adverse effect of propylthiouracil, and most cases of agranulocytosis appear to occur within the first 2 months of therapy, but rarely may occur after 4 months of therapy. The risk of propylthiouracil-induced agranulocytosis appears to be substantially increased in patients older than 40 years of age compared with younger patients, but, unlike methimazole, an association with dosage has not been established. Although the mechanism(s) of propylthiouracil-induced agranulocytosis has not been determined, antigranulocyte antibodies have been reported in some patients with thioamide-induced agranulocytosis; a direct toxic effect of these drugs on bone marrow has not been excluded as an additional possible cause.|Propylthiouracil crosses the placenta and may cause fetal harm when administered to pregnant women; the drug can induce goiter and hypothyroidism (cretinism) in the developing fetus. If the drug is used during pregnancy for the management of hyperthyroidism, the manufacturer states that careful dosage adjustment, using a sufficient but not excessive dosage of propylthiouracil, is necessary. The manufacturer states that because thyroid dysfunction diminishes in many women as pregnancy proceeds, a reduction in dosage may be possible, and, in some patients, propylthiouracil can be discontinued 2 or 3 weeks before delivery. If propylthiouracil is used during pregnancy, or if a woman becomes pregnant while receiving the drug, she should be advised of the potential hazard to the fetus.|... Disagreement about therapy of thyrotoxicosis during pregnancy. Antithyroid drugs cross placenta and can cause fetal hypothyroidism and goiter. ... There are 3 choices of therapy, each with its advocates: minimal doses of antithyroid drugs, full doses ... with thyroid hormone supplementation, or surgery. /Antithyroid drugs/|For more Drug Warnings (Complete) data for PROPYL THIOURACIL (20 total), please visit the HSDB record page.

Propylthiouracil is a thiourea antithyroid agent. Grave's disease is the most common cause of hyperthyroidism. It is an autoimmune disease where an individual's own antibodies attach to thyroid stimulating hormone receptors within cells of the thyroid gland and then trigger overproduction of thyroid hormone. The two thyroid hormones manufactured by the thyroid gland, thyroxine (T4) and triiodothyronine (T3), are formed by combining iodine and a protein called thyroglobulin with the assistance of an enzyme called peroxidase. PTU inhibits iodine and peroxidase from their normal interactions with thyroglobulin to form T4 and T3. This action decreases thyroid hormone production. PTU also interferes with the conversion of T4 to T3, and, since T3 is more potent than T4, this also reduces the activity of thyroid hormones. The actions and use of propylthiouracil are similar to those of methimazole.

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Antimetabolites.)|Agents that are used to treat hyperthyroidism by reducing the excessive production of thyroid hormones. (See all compounds classified as Antithyroid Agents.)

Well absorbed following oral administration.|Propylthiouracil is readily absorbed and is extensively metabolized. Approximately 35% of the drug is excreted in the urine, in intact and conjugated forms, within 24 hours.|Elimination: Less than 1% is excreted in the urine unchanged. Total body clearance is approximately 7 L/hr. In dialysis: Elimination and pharmacokinetics are not significantly altered in hemodialysis. In one patient undergoing hemodialysis, 5% of a 200 mg oral dose was removed by 3 hours of hemodialysis; elimination rate was not significantly altered. Peak serum concentration was decreased (from 7.9 to 4.9 ug/mL), although it remained within an approximate therapeutic range.|Although distribution of propylthiouracil into human body tissues and fluids has not been fully characterized, the drug appears to be concentrated in the thyroid gland. Propylthiouracil readily crosses the placenta. Propylthiouracil is distributed into milk; however, some studies indicate that the extent of distribution is only about 0.007-0.077% of a single dose.|Propylthiouracil is rapidly and readily absorbed from the GI tract following oral administration with peak plasma concentrations of about 6-9 mcg/mL occurring within 1-1.5 hours after a single dose of 200-400 mg. In one study in which the drug was administered orally and IV, about 75% of the oral dose was absorbed. Plasma concentrations of the drug do not appear to correlate with the therapeutic effects.|Time to peak effect: 17 weeks (average) to normalize serum T3 and T4 concentrations with use of 300 mg/day.|For more Absorption, Distribution and Excretion (Complete) data for PROPYL THIOURACIL (19 total), please visit the HSDB record page.

Propylthiouracil was concentrated by thyroid gland, and four sulfur-35 compounds were demonstrated by TLC in both rat and man: unchanged propylthiouracil, (35)-sulfate, unknown propylthiouracil metabolite and protein-bound sulfur-35...|Biotransformation: Primarily undergoes glucuronidation. Approximately 33% of an orally administered dose is metabolized by a first-pass effect.|Presence of more than one glucuronide conjugate of propylthiouracil ought to be expected, as it has four functional groups, each capable of conjugation with glucuronic acid ...|Although the exact metabolic fate of propylthiouracil has not been fully established, the drug is rapidly metabolized to its glucuronide conjugate and other minor metabolites and requires frequent administration to maintain its antithyroid effect. The drug and its metabolites are excreted in urine, with about 35% of a dose excreted within 24 hours.|For more Metabolism/Metabolites (Complete) data for PROPYL THIOURACIL (8 total), please visit the HSDB record page.

2 hours|The elimination half-life of propylthiouracil has generally been reported to be about 1-2 hours.|The plasma half-life of propylthiouracil .../is/ 1 to 2 hours.|/After GI absorption/ plasma half-lives of 2.5 hr (human) and 4.8 hr (rat) have been reported ... .|The half-life of propylthiouracil in plasma is about 75 min ...|Propylthiouracil is rapidly absorbed from /orally/ dosed tablets in man, yielding max plasma levels at 60-120 min, and biological t/2 of about 60 min in euthyroid subjects.

Propylthiouracil binds to thyroid peroxidase and thereby inhibits the conversion of iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (via hydrogen peroxide as a cofactor) and also catalyzes the incorporation of the resulting iodide molecule onto both the 3 and/or 5 positions of the phenol rings of tyrosines found in thyroglobulin. Thyroglobulin is degraded to produce thyroxine (T4) and tri-iodothyronine (T3), which are the main hormones produced by the thyroid gland. Therefore propylthiouracil effectively inhibits the production of new thyroid hormones.|Propylthiouracil inhibits the synthesis of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; the drug also inhibits the coupling of these iodotyrosyl residues to form iodothyronine. Although the exact mechanism(s) has not been fully elucidated, propylthiouracil may interfere with the oxidation of iodide ion and iodotyrosyl groups. Based on limited evidence it appears that the coupling reaction is more sensitive to antithyroid agents than the iodination reaction. Propylthiouracil does not inhibit the action of thyroid hormones already formed and present in the thyroid gland or circulation nor does the drug interfere with the effectiveness of exogenously administered thyroid hormones. Patients whose thyroid gland contains relatively high concentration of iodine (e.g., from prior ingestion or from administration during diagnostic radiologic procedures) may respond relatively slowly to antithyroid agents. Unlike methimazole, propylthiouracil inhibits the peripheral deiodination of thyroxine to triiodothyronine. Although the importance of this inhibition has not been established, propylthiouracil has a theoretical advantage compared with methimazole or carbimazole in patients with thyrotoxic crisis, since a decreased rate of conversion of circulating thyroxine to triiodothyronine may be clinically beneficial in these patients.|The thionamide /propylthiouracil/ inhibit organification of iodide and the coupling of iodotyrosines to form hormonally active iodothyronines.|Inhibit synthesis of thyroid hormone within the thyroid gland by serving as substrates for thyroid peroxidase, which catalyzes the incorporation of oxidized iodide into tyrosine residues in thyroglobulin molecules and couples iodotyrosines. This diverts iodine from the synthesis of thyroid hormones. Antithyroid agents do not interfere with the actions of exogenous thyroid hormone or inhibit the release of thyroid hormones. Therefore, stores of thyroid hormones must be depleted before clinical effects will be apparent. Antithyroid agents may also have moderating effects on the underlying immunologic abnormalities, in hyperthyroidism due to Graves' disease (toxic-diffuse goiter), but evidence on this point reported to date is inconclusive.|Type I 5'-deiodinase (D1) is inhibited by ... the antithyroid drug propylthiouracil.|For more Mechanism of Action (Complete) data for PROPYL THIOURACIL (9 total), please visit the HSDB record page.

... Small amounts of thiourea present as an impurity.|Small amounts of thiourea may be present in propylthiouracil as an impurity.

SYMPTOMS: Symptoms of exposure to this compound include recurrent painful skin lesions, fatigue, migratory polyanthralgias of hands and knees, palpable spleen, splenomegaly, amenorrhea, low-grade fever, gingivostomatitis, weakness, weight loss, dark red-brown colored urine, necrotizing vasculitis, leukopenia, cutaneous vasculitis, nasal congestion, enlarged thyroid, necrotic ulcerations on the lower extremities, bloody nasal discharge and cough. Other symptoms include fever, sore throat, rash and malaise. The most serious reaction to this chemical may be agranulocytosis. It may also cause pain and stiffness in the joints, paresthesias, headache, nausea and loss or depigmentation of hair. On rare occasions, exposure to this material may cause drug fever, hepatitis and nephritis. Other symptoms include urticaria, anorexia, hypoprothrombinemia with purpura and hepatic injury. Exposure may also cause a tendency to hemorrhage, lupus-like syndrome, hypothyroidism, galactorrhea, migratory polyarthritis, reversible tinnitus, hearing loss, hypocalcemia, jaundice, hepatic necrosis and liver disease similar to chronic active hepatitis. It may also cause goiter in infants born to women following exposure to this compound. ACUTE/CHRONIC HAZARDS: It is harmful if swallowed, inhaled or absorbed through the skin. It may cause irritation. When heated to decomposition, this compound emits very toxic fumes of SOx and NOx. It may also emit toxic fumes of carbon monoxide and carbon dioxide. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ In a survey of 331 hyperthyroid patients treated with antithyroid drugs and later with thyroidectomy, four malignant thyroid lesions were detected in patients diagnosed with Grave's disease, whose drug therapy had continued for at least 1 year.|/OTHER TOXICITY INFORMATION/ In humans, hypothyroidism causes irreversible mental retardation and various neuromotor disabilities.|/SIGNS AND SYMPTOMS/ Other rare but serious reactions include toxic hepatitis, vasculitis (often antineutrophil cytoplasmic antibody-positive) and a drug-induced lupus syndrome.|/SIGNS AND SYMPTOMS/ In general, overdosage of propylthiouracil may be expected to produce effects that are extensions of common adverse reactions. Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia have been reported. Agranulocytosis is the most serious adverse effect associated with propylthiouracil overdosage. Exfoliative dermatitis and hepatitis have also occurred.|For more Human Toxicity Excerpts (Complete) data for PROPYL THIOURACIL (18 total), please visit the HSDB record page.

6 Propyl 2 Thiouracil

Propylthiouracil is available in US as USP grade containing 98-100.5% active ingredient on dried basis...|Oral: Tablets 50 mg (available by nonproprietary name)

4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo-: ACTIVE

IT MAY...BE DETERMINED IN.../PHARMACEUTICAL/ PREPN BY POTENTIOMETRIC TITRATION EMPLOYING 0.1 N CHLORAMINE T &...EST IN FEED MATERIAL BY CHROMATOGRAPHY OVER SILICA GEL G (SENSITIVITY, 1 UG).|The colorimetric method of McAllister & Howells (1952) employing 2,6-dichloroquinone chloroimide reagent at pH 8.0 has been modified to measure propylthiouracil concentrations of 0.5-10 ug/ml in serum. ... Propylthiouracil, thiourea and sulphate were separated by thin-layer chromatography on cellulose and silica gel plates using the solvent systems ethanol:1M ammonium acetate and chloroform:methanol:water respectively.|Method: AOAC 952.27; Procedure: spectrophotometric method; Analyte: propyl thiouracil; Matrix: drugs; Detection Limit: not provided.|Method: EPA-OSW 8270D; Procedure: gas chromatography/mass spectrometry; Analyte: propyl thiouracil; Matrix: solid waste matrices, soils, air sampling media and water samples; Detection Limit: 100 ug/L.|For more Analytic Laboratory Methods (Complete) data for PROPYL THIOURACIL (9 total), please visit the HSDB record page.

HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC DETERMINATION OF PLASMA PROPYLTHIOURACIL; TWO HPLC PROCEDURES FOR DETERMINING PROPYL THIOURACIL IN HUMAN PLASMA ARE DISCUSSED.|HPLC PROCEDURES FOR DETERMINING PROPYL THIOURACIL IN HUMAN PLASMA ARE DISCUSSED.|Analyte: propylthiouracil; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 214 nm; limit of detection: 40 ng/mL|Analyte: propylthiouracil; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 276 nm; limit of detection: 200 ng/mL|Analyte: propylthiouracil; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 275 nm; limit of detection: 5 ng/mL

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals