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Pharmaceuticals -> Antibiotics (Sulfonamide)

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

log Kow = 0.54

0.9

0.26

Crystals from water

Colorless crystal

Insoluble at pH 6.5 (=10mg/ml). (NTP, 1992)

1 g dissolves in: 4000 mL water at pH 6.5, 5 mL water at pH 7.5, 40 g methanol, 30 g ethanol, 10 g acetone, 1370 g ether, 2800 g chloroform; practically insol in benzene

Slightly soluble in hot water

In water, 105 mg/L at 37 °C

6.11e-01 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

FDA approved animal drugs -> Active ingredient

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan

406 °F (NTP, 1992)

210 °C

208 °C

Sulfamethizole is a white powder. (NTP, 1992)

Solid

152.2 Ų [M+H]+ [CCS Type: TW]

166.52 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

171.2 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with Waters Major Mix]

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

Warning

H317 (98.8%): May cause an allergic skin reaction [Warning Sensitization, Skin]

P261, P272, P280, P302+P352, P321, P333+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 81 reports by companies from 3 notifications to the ECHA C&L Inventory.

Oral dosage form new animal drugs. Sulfamethizole and methenamine mandelate tablets. ... Each tablet contains 250 milligrams of sulfamethizole and 250 milligrams of methenamine mandelate. ... Conditions of use. (1) The drug is indicated for the treatment of urinary tract infections in dogs and cats such as cystitis, nephritis, prostatitis, urethritis, and pyelonephritis. It is also used as an aid in the management of complications resulting from surgical manipulations of the urinary tract such as removal of calculi from the bladder, in ureterostomies, and in instrumentation of the urethra and bladder. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. /Sulfamethizole and methenamine mandelate tablets/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Sulfamethizole is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Sulfamethizole is included on this list.

This compound is not very flammable but any fire involving this compound may produce dangerous vapors. You should evacuate the area. All firefighters should wear full-body protective clothing and use self-contained breathing apparatuses. You should extinguish any fires involving this chemical with a dry chemical, carbon dioxide, foam, or halon extinguisher. (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. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital.

Sulfamethizole should be store in well-closed containers.

Most sulfonamides slowly darken on exposure to light and should be stored in tight, light-resistant containers. /Sulfonamides/

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, you should dampen the solid spill material with alcohol, then transfer the dampened material to a suitable container. Use absorbent paper dampened with alcohol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with alcohol followed by washing with a strong soap and water solution. Do not reenter the contaminate area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

These medications /coumarin- or indandione-derivative anticoagulants; hydantoin anticonvulsants or oral antidiabetic agents/ may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy. /Sulfonamides/

Concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered. /Sulfonamides/

Concurrent long-term use of sulfonamides /with estrogen-containing, oral contraceptives/ may result in increased incidence of breakthrough bleeding and pregnancy. /Sulfonamides/

Concurrent use /of cyclosporine/ with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentration and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored. /Sulfonamides/

For more Interactions (Complete) data for SULFAMETHIZOLE (12 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 47(SRC), determined from a log Kow of 0.54(2) and a regression-derived equation(3), indicates that sulfamethizole is expected to have very high mobility in soil(SRC). The pKa1 and pKa2 values for sulfamethizole are 2.1 and 5.3(4), respectively, indicating that this compound will partially exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization of the neutral species from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.6X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(6). Sulfamethizole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-9 mm Hg(SRC), determined from a fragment constant method(7). In general, sulfonamide antimicrobials are not readily biodegraded and persist in soils(8).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 47(SRC), determined from a log Kow of 0.54(2) and a regression-derived equation(3), indicates that sulfamethizole is not expected to adsorb to suspended solids and sediment(SRC). A pKa1 and pKa2 of 2.1 and 5.3(4), respectively, indicate sulfamethizole will exist partially in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(5). By analogy to structurally similar sulfamethoxazole which did not undergo hydrolysis under field conditions(9), hydrolysis of sulfamethizole is not expected to be an important environmental fate process(SRC). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). In general, sulfonamide antimicrobials are not readily biodegraded(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sulfamethizole, which has an estimated vapor pressure of 2.1X10-9 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 sulfamethizole may be removed from the air by wet or dry deposition(SRC). Sulfamethizole contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=144-82-1][Available from: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=144-82-1]

Leachate samples were collected on September 6, 2000, down gradient from the Norman Municipal Landfill research site in central Oklahoma; the landfill was established in the 1920s and closed in 1985(1). Sulfamethizole was tested for but not detected, reporting limit 0.10 ug/L(1). Sulfamethizole was not detected in final effluents of eight wastewater treatment plants in five Canadian cities, sampled in 2002; detection limit 0.004 ug/L(2). The compound has been detected in the secondary effluent of a waste water treatment plant in Berlin, Germany at a concentration of 0.006 ug/L(2).

The Koc of sulfamethizole is estimated as 47(SRC), using a log Kow of 0.54(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that sulfamethizole is expected to have very high mobility in soil. The pKa1 and pKa2 for sulfamethizole are 2.1 and 5.3(4), respectively, indicating that this compound will partially exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(6,7), suggesting that mobility may be much lower in some soils(SRC). Treated waste water effluent containing sulfamethizole was applied to soil columns over 23 days; the compound was not detected (detection limit 0.05 ug/L) in the drainage samples(8).

/SIGNS AND SYMPTOMS/ The acute signs and symptoms associated with sulfonamide overdosage include anorexia, nausea, and colicky abdominal pain, vertigo, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria have been reported. Blood dyscrasias and jaundice are late manifestations of overdose.

/CASE REPORTS/ Case report of a 50-yr-old man with renal dysfunction who developed oxidant hemolysis while on sulfamethizole therapy is described.

/EPIDEMIOLOGY STUDIES/ Eleven hundred cases of drug induced liver disease have been reported in Denmark from 1978 to 1987, including 52 fatal cases. Approximately 100 new cases have been reported every year since 1987. The definition and classification of drug induced liver disease are presented together with a review of the most common patho-anatomical pictures and pathogenic mechanisms, followed by a description of symptoms and paraclinical abnormalities for each of the ten most common drugs causing serious liver disease. Individual cases of liver disease caused by paracetamol, sulfamethizole and androgenic steroid hormones are presented. ... Finally there are some proposals for diminishing the number of and the severity of drug induced liver disease.

/EPIDEMIOLOGY STUDIES/ ... The risk of adverse birth and neonatal outcome, and miscarriage in women who used sulfamethizole during pregnancy /was investigated/. The association between use of sulfamethizole and adverse birth and neonatal outcome was investigated in a case-control and a cohort study in Denmark. /Investigators/ used data from the Prescription Database, the Birth Registry and the Hospital Discharge Registry in North Jutland County to study any association between sulfamethizole use and first recorded miscarriage. The cohort analysis included 3484 women who received a prescription for sulfamethizole from 30 days before conception to date of delivery, and 60175 women who did not use a sulphonamide-containing drug during pregnancy or 30 days before conception. The case-control analysis included 3347 women who had a miscarriage, of whom 90 had taken sulfamethizole, and 22599 primiparous controls who had a live birth. Among women who received prescriptions for sulfamethizole, adjusted odds ratios and 95% confidence intervals for adverse birth outcome were: malformation 1.17 (0.95-1.43); low birth weight 0.69 (0.49-0.98); pre-term birth 1.12 (0.97-1.30); stillbirth 1.02 (0.61-1.68); neonatal jaundice 1.14 (0.38-3.46); and for receiving a prescription for sulfamethizole within 1 week before miscarriage 1.66 (0.92-2.99). /Investigators/ found no increased risk of congenital malformation, stillbirth or pre-term birth, and no association between use of sulfamethizole late in pregnancy and risk of neonatal jaundice. There was an increased risk of miscarriage after exposure to sulfamethizole during the week before miscarriage, but further studies are needed to evaluate whether this increased risk is causal.

/OTHER TOXICITY INFORMATION/ Various dermatologic reactions, including rash, pruritus, urticaria, erythema nodosum, erythema multiforme (Stevens-Johnson syndrome), Lyell's syndrome (may be associated with corneal damage), Behcet's syndrome, toxic epidermal necrolysis, and exfoliative dermatitis, have been reported in patients receiving sulfonamides. Because photosensitivity may also occur, patients should be cautioned against exposure to UV light or prolonged exposure to sunlight. A relatively high proportion of fatalities has occurred as a result of the Stevens-Johnson syndrome, especially in children. Although long-acting sulfonamides (which are no longer commercially available) have been associated most often with the Stevens-Johnson syndrome, other sulfonamides also have been reported to cause this reaction. The physician should be alert to the signs, including high fever, severe headache, stomatitis, conjunctivitis, rhinitis, urethritis, and balanitis, which may precede the onset of the cutaneous lesions of the Stevens-Johnson syndrome. If a rash develops during therapy, the sulfonamide should be discontinued at once. In rare instances, a skin rash may precede a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and/or serious blood disorders. /Sulfonamides/

Drug Induced Liver Injury Rank (DILIrank 2.0)

Sulfamethizole

vLess-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 3 was calculated in fish for sulfamethizole(SRC), using a log Kow of 0.54(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for the neutral species of sulfamethizole is estimated as 2.6X10-14 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that the neutral species is expected to be essentially nonvolatile from moist soil surfaces(2). A pKa1 and pKa2 of 2.1 and 5.3(3), respectively, indicate sulfamethizole will exist partially in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(4). Sulfamethizole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-9 mm Hg(SRC), determined from a fragment constant method(5).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides, and long-term administration has produce thyroid malignancies in the species.

/GENOTOXICITY/ Sulfamethiazole was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Sulfamethiazole was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.001, 0.003, 0.0033, 0.010, 0.033, 0.100, 0.200, and 0.333 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 0.333 mg/plate.

Oral dosage form new animal drugs. Sulfamethizole and methenamine mandelate tablets. ... Each tablet contains 250 milligrams of sulfamethizole and 250 milligrams of methenamine mandelate. ... Conditions of use. (1) The drug is indicated for the treatment of urinary tract infections in dogs and cats such as cystitis, nephritis, prostatitis, urethritis, and pyelonephritis. It is also used as an aid in the management of complications resulting from surgical manipulations of the urinary tract such as removal of calculi from the bladder, in ureterostomies, and in instrumentation of the urethra and bladder. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. /Sulfamethizole and methenamine mandelate tablets/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Sulfamethizole is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Sulfamethizole is included on this list.

S - Sensory organs

D - Dermatologicals

B - Blood and blood forming organs

J - Antiinfectives for systemic use

QB - Blood and blood forming organs

QS - Sensory organs

Sulfamethizole is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organisms. However, many strains of an individual species may be resistant. Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of <i>p</i>-aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally. However, parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus.

Sulfamethizole is a competitive inhibitor of bacterial enzyme dihydropteroate synthetase. The normal para-aminobenzoic acid (PABA) substrate is prevented from binding. The inhibited reaction is necessary in these organisms for the synthesis of folic acid.

Sulfonamides are usually bacteriostatic in action. Sulfonamides interfere with the utilization of p-aminobenzoic acid (PABA) in the biosynthesis of tetrahydrofolic acid (the reduced form of folic acid) cofactors in susceptible bacteria. Sulfonamides are structural analogs of PABA and appear to interfere with PABA utilization by competitively inhibiting the enzyme dihydropteroate synthase, which catalyzes the formation of dihydropteroic acid (a precursor of tetrahydrofolic acid) from PABA and pteridine; however, other mechanism(s) affecting the biosynthetic pathway also may be involved. Compounds such as pyrimethamine and trimethoprim, which block later stages in the synthesis of folic acid, act synergistically with sulfonamides. Only microorganisms that synthesize their own folic acid are inhibited by sulfonamides; animal cells and bacteria which are capable of utilizing folic acid precursors or preformed folic acid are not affected by these drugs. The antibacterial activity of the sulfonamides is reportedly decreased in the presence of blood or purulent body exudates. /Sulfonamides/

The sulfonamides are structural analogs of para-aminobenzoic acid (PABA) and competitively inhibit an enzymatic step (dihydropterate synthetase) during which PABA is incorporated into the synthesis of dihydrofolic acid (folic acid). Because dihydrofolate synthesis is reduced, the levels of tetrahydrofolate (folinic acid) formed from dihydrofolate diminish. Tetrahydrofolate is an essential component of the coenzymes responsible for single carbon metabolism in cells. Acting as antimetabolites to PABA, sulfonamides eventually block, in a complex fashion, several enzymes. These enzymes include those needed for the biogenesis of purine bases; for the transfer of desoxyuridine to thymidine; and for the biosynthesis of methionine, glycine, and formylmethionyl-transfer-RNA. This results in suppression of protein synthesis, impairment of metabolic processes, and inhibition of growth and multiplication of those organisms that cannot use preformed folate. The effect is bacteriostatic, although a bactericidal action is evident at the high concentrations that may be found in urine.

3-8 hours

Sulfonamides are generally classified as short-acting, intermediate-acting, or long-acting depending on the rate at which they are absorbed and eliminated. Sulfamethizole, sulfasalazine, and sulfisoxazole are generally considered to be short-acting sulfonamides and reportedly have plasma half-lives of about 4-8 hours. Sulfadiazine and sulfapyridine are generally considered to be intermediate-acting sulfonamides and reportedly have plasma half-lives of about 7-17 hours. /Sulfonamides/

Hepatic.

Approximately 95% of a given dose of sulfamethizole is not metabolized; less than 5% is acetylated. As a consequence, almost all of a given dose of sulfamethizole is present in its active form in the body.

Renal clearance values of metabolite N4-acetylsulfonamides are 6-20 times higher than their parent compd. Sulfamethizole is acetylated very little.

Although the liver is the major site of metabolism, sulfonamides may also be metabolized in other body tissues. Most sulfonamides are metabolized mainly by N4-acetylation. The degree of acetylation, which is a function of time, varies from less than 5% for sulfamethizole to up to 40% for sulfadiazine. The N4-acetyl metabolites, which do not possess antibacterial activity, have greater affinity for plasma albumin than does the nonacetylated drug and are usually less soluble than the parent sulfonamide, particularly in acidic urine. Like acetyl derivatives, glucuronide derivatives do not possess antibacterial activity; however, glucuronide derivatives are water soluble, appear to resemble the nonacetylated sulfonamide in plasma binding capacity, and have not been associated with adverse effects. /Sulfonamides/

Rapidly absorbed.

Sulfamethizole is readily absorbed form the GI tract. Following oral administration of a single 2-g dose of sulfamethizole in a limited number of patients, blood concentrations of approximately 30 ug/mL were attained within 1 hour. Peak blood concentrations of about 60 ug/mL were reached within 2 hours followed by a gradual decrease to 6.6 ug/mL within eight hours and to 5 ug/mL within 12 hours. Approximately 2-11% of sulfamethizole present in the blood is in the N4-acetylated form.

Sulfamethizole is distributed into most body tissues but does not appear to diffuse into the CSF of patients with normal meninges. Sulfamethizole is approximately 90% bound to plasma proteins. Since the drug is rapidly eliminated in urine, the manufacturer states that accumulation of sulfamethizole in tissues outside the urinary tract is minimal

Sulfamethizole...is a rapidly eliminated sulfonamide; concentrations of drug in blood are thus low after administration of conventional doses.

Approximately 80% of an administered dose is recoverable within eight hours; approximately 98% is cleared in 15 to 24 hours. Sulfamethizole is cleared by the kidney at a rate only 10 to 20% lower than that of creatinine.

For more Absorption, Distribution and Excretion (Complete) data for SULFAMETHIZOLE (21 total), please visit the HSDB record page.

THERAP CAT: Antibacterial

THERAP CAT (VET): Antibacterial

MEDICATION

MEDICATION (VET)

Oral tablets: 500 mg (sulfamethizole), Thiosulfil Forte (scored), Wyeth-Ayerst

MARKETED AS A 4% AQUEOUS SOLN, PH 7.3-7.4. /SODIUM SALT/

SULFAMETHIZOLE IS AVAILABLE IN TABLETS CONTAINING 250, 500, OR 1000 MG & IN SUSPENSIONS OF 250 MG/5 ML OR 500 MG/5 ML.

Thiosnifil-A (Ayerst), Proklar (O'Neal, Jones & Feldman), component of Azotrex (Bristol), and component of Suladyne (Reid-Provident).