Sulfamethazine (80 mg/kg; intravenous injection; healthy sows) treatment resulted in a single intramuscular dose of 80 mg/kg sulfamethoxazine, which considerably increased t1/2α, Vd, and CIB and dramatically decreased α, β, and AUC0->∞. Pigs have an absolute bioavailability of 1.01 [1].

Animal/Disease Models: 19 healthy sows (6 weeks old, 4.5-6.2 kg) [1]
Doses: 80 mg/kg
Route of Administration: intravenous (iv) (iv)injection (pharmacokinetic/PK/PK study)
Experimental Results: The half-life of the distribution period is 0.23 hrs (hrs (hours)) and a half - The lifetime of the elimination phase is 9.8 hrs (hrs (hours)). α, β and AUC0->∞ were Dramatically diminished, t1/2α, Vd and CIB were Dramatically increased, and the absolute bioavailability in pigs was 1.01.

Absorption, Distribution and Excretion
Rapid absorption after oral administration.
This study investigated the pharmacokinetics and metabolism of sulfadiazine (SDM) after intravenous administration in seven 12-week-old pre-ruminant lambs and 18-week-old ruminant lambs. Compared to 12-week-old lambs, 18-week-old lambs exhibited a longer duration of SDM elimination: older lambs showed lower systemic clearance and a longer elimination time for SDM. Renal clearance of SDM and its metabolites was similar in both age groups. The decreased SDM clearance was associated with a significant reduction in SDM hydroxylation in older lambs. Sexual maturation in children may lead to decreased hepatic oxidative metabolism.
This study performed sulfadiazine acetylation phenotype assays in 19 healthy adults (aged 17–46 years; 15 males, 4 females; 9 Caucasians, 9 Asians, and 1 Black individual) who received a single oral dose of 20 mg/kg body weight of sulfadiazine (dissolved in 200 mL of water). The results showed that both acetylation clearance and overall elimination or metabolic rate constant exhibited a clear trimodal pattern, confirming that the rapid acetylation phenotype could be further subdivided into intermediate acetylation and rapid acetylation groups. The mean acetylation clearance rate in the rapid acetylation group (1.34 mL/min/kg body weight) was 8.8 times that of the slow acetylation group (0.15 mL/min/kg body weight) and 1.8 times that of the intermediate acetylation group (0.75 mL/min/kg body weight). The mean percentage of the absorbed dose excreted in the urine as acesulfame potassium in the 72-hour period was 93.7% in the rapid acetylation group, 87.7% in the intermediate acetylation group, and 65.6% in the slow acetylation group. This study investigated the consumption of SDM and its N4-acetyl and hydroxyl metabolites in eggs produced by hens after single or multiple oral administrations of 100 mg/kg sulfadiazine (SDM). During the administration period and within 1 day after the last administration, the concentrations of SDM and its metabolites in egg white were higher than those in egg yolk, consistent with plasma concentrations. Starting 2 days after the last administration, the concentration of SDM in egg yolk was higher than that in egg white, and the drug consumption curves showed a parallel relationship. The average maximum SDM content in the whole egg after a single administration was 1500 μg; after multiple administrations, the average maximum content was 1280 μg. Trace amounts of N4-acetyl and 6-methylhydroxy metabolites were detected in the egg (mainly in egg white), at concentrations approximately 1/40 of the parent drug. A highly significant correlation was found between the developmental stage of the oocyte at the time of the (last) administration and the sulfadiazine (SDM) content in the resulting oocytes (P<0.005). It took 7 to 8 days after the (last) administration of a dose of 100 mg SDM/kg/day to reduce SDM levels below 0.1 μg/g oocyte. A relatively strong blood-brain barrier was observed in rats. Sulfamethazine is transported slowly and difficultly from the blood to the brain. For more complete data on the absorption, distribution, and excretion of sulfadimidines (12 in total), please visit the HSDB records page. Metabolites/Metabolites This study investigated the plasma distribution of sulfadimidine (SDM) and its metabolites in laying hens. Hens were administered 100 mg/kg SDM via single intravenous injection, single oral administration, and multiple oral administrations once daily for 5 consecutive days. SDM is primarily metabolized via acetylation and hydroxylation. The highest concentration of the metabolite in plasma was N4-acetylsulfadimidine (N4-SDM), followed by hydroxymethylsulfadimidine (CH2OH) and 5-hydroxysulfadimidine. Following intravenous administration, SDM and its metabolites exhibited a biphasic elimination pattern (characterized by a volume-limiting response). Following multiple (5) doses of SDM, plasma SDM concentrations ranged from 7 to 108 μg/mL; within 96 hours after the end of the multiple doses, plasma SDM concentrations were below 0.01 μg/mL. The renal clearance of N4-SDM and its hydroxyl metabolites was approximately 10 times that of SDM. SDM mass balance (fecal/urine recovery) showed a 56% loss after intravenous administration and a 67% loss after a single oral dose; hydroxyl metabolites accounted for the highest proportion in feces/urine. Therefore, other metabolic pathways must exist in laying hens.
In 10 male and 2 female healthy volunteers, after oral administration of 12-17 mg/kg body weight of sulfadiazine, 10-20% of the dose was excreted in urine as free and conjugated hydroxylated metabolites, and 61-81% was excreted as N4-acetylsulfadiazine. Six volunteers were considered rapid acetylaters, and six were considered slow acetylaters. Plasma concentration-time curves of sulfadiazine in rapidly acetylated individuals were biphasic, with half-lives of 1.7 hours and 5.4 hours, respectively; while those in slowly acetylated individuals were monophasic, with a half-life of 7.6 hours. Sulfadiazine is metabolized similarly in animals and humans, primarily via N4-acetylation. In humans, sulfadiazine acetylation exhibits a trimodal pattern. Differences in acetylation rates were observed between male and female rats, as well as between different strains of female rats. The pharmacokinetics of sulfamethoxazole, sulfamethoxazole, sulfadiazine, sulfapyridine, and sulfadiazine have been studied in humans. The renal clearance of the metabolite N4-acetylsulamide is 6 to 20 times higher than that of the corresponding parent compounds. The renal clearance of sulfonamides depends on urine flow rate. Plasma and urine concentration-time curves of N4-acetylsulamide for sulfonamides have been constructed. Percentage-time curves of N4-acetylsulfadiazine in plasma are a valid tool for determining the acetylation phenotype, while curves constructed from urine samples are less suitable. Evidence suggests that sulfadiazine is metabolized by two different isoenzymes, while sulfadiazine, sulfapyridine, and sulfamethoxazole are metabolized by a single acetylation isoenzyme. Sulfamethoxazole is minimally acetylated. For more complete metabolite/metabolite data on sulfadiazine (9 metabolites in total), please visit the HSDB record page.
Biological Half-Life
Following oral administration of 12–17 mg/kg body weight of sulfadiazine to 10 healthy male and 2 healthy female volunteers, 10–20% of the dose was excreted in the urine as free and bound hydroxylated metabolites, and 61–81% as N4-acetylsulfadiazine. Six subjects were considered rapid acetylaters, and six were considered slow acetylaters. In rapid acetylated individuals, the plasma concentration-time curve of sulfadimidine was biphasic, with half-lives of 1.7 hours and 5.4 hours, respectively; while in slow acetylated individuals, the curve was monophasic, with a half-life of 7.6 hours. Sulfamethidine can undergo acetylation and hydroxylation in humans. ... In rapid acetylated individuals, the plasma concentration-time curve of sulfadimidine was biphasic, with half-lives of 1.7 hours and 5.4 hours, respectively; while in slow acetylated individuals, the curve was monophasic, with a half-life of 7.6 hours. ... ... / After oral administration to pigs, / the mean half-lives of sulfadimidine, its N4-glucose conjugate, and N4-acetylsulfadimidine were estimated to be 0.8 days. ...

Toxicity Summary
Identification and Uses: Sulfamethazine (SMZ) is a milky white powder or crystals. It is an anti-infective drug used in veterinary medicine. Sulfamethazine is used as a broad-spectrum antibacterial agent to treat or prevent infections caused by susceptible microorganisms. Infections treated include pneumonia, intestinal infections (especially coccidiosis), soft tissue infections, and urinary tract infections. Human Exposure and Toxicity: Sulfamethazine did not induce unplanned DNA synthesis in cultured human fibroblasts in vitro. Animal Studies: In rats fed a diet containing 600 mg/kg sulfadiazine, some rats developed thyroid hyperplasia and mild hypertrophy at weeks 4 and 8, but this was not observed at week 13. These changes in the thyroid gland completely resolved after the recovery period. In normal rats, feeding diets containing 2400 and 4800 mg/kg sulfadiazine significantly increased both the absolute and relative weight of the thyroid gland. In pituitary-resected rats, the relative weight of the thyroid gland was slightly lower than that of the normal control group, but no effect of sulfadiazine treatment was observed. Follicular cell hypertrophy and hyperplasia induced by sulfadiazine treatment were observed in normal rats. No thyroid morphological changes were observed in pituitary-resected rats (without thyroid-stimulating hormone TSH) administered sulfadimidine (SMZ). In vitro, sulfadimidine did not increase thyroid cell proliferation in the absence of TSH and had no effect on thyroid structure/function in cynomolgus monkeys administered sulfadimidine. Non-human primates and humans are known to have greater resistance to thyroid peroxidase inhibitors than rodents. Female mice were fed a control diet or a diet containing 300, 600, 1200, 2400, or 3600 mg/kg sulfadimidine for 90 days. No treatment-related lesions were observed in mice, either macroscopically or microscopically. Two years later, high-dose (4800 ppm) mice showed an increased incidence of thyroid tumors in both male and female mice, while this was not observed in the low-dose group. To determine the toxicity and potential carcinogenicity of sulfadimidine, rats were fed diets containing 10, 40, 600, 1200, or 2400 ppm of sulfadimidine. In animals sacrificed after 24 months, a statistically significant dose-dependent increase in the incidence of thyroid follicular cell adenocarcinoma was observed. The incidence of non-neoplastic thyroid lesions was significantly higher in the treatment groups than in the control group. These lesions included follicular cell hyperplasia, focal cellular changes in follicular cells, and multilocular cysts. The incidence of retinal atrophy and acinar pancreatic atrophy (males) also increased with increasing sulfadimidine (SMZ) doses. In several avian species, SMZ exposure led to elevated plasma gonadotropin and prolactin levels. In mice fed 1% sulfadiazine, no treatment-related histopathological changes were observed in the pituitary gland or reproductive organs of either male or female mice. Rats were administered sulfadiazine by gavage at doses of 0, 540, 680, or 860 mg/kg body weight/day during days 6–15 of gestation. Weight gain was reduced in all tested dams, with an increase in relative liver weight. In the high-dose groups, fetal weight decreased, and the number of malformed fetuses per litter increased. The incidence of gross or visceral malformations in fetuses/litters was increased, with cleft palate, hydroureter, and hydronephrosis being the most common. The incidence of hydroureter and hydronephrosis was also increased in the medium-dose groups. The mutagenicity of sulfadiazine was assessed in five Salmonella typhimurium strains (TA 1535, TA 1537, TA 97, TA 98, and TA 100) using a Salmonella/microsomal pre-incubation assay with or without metabolic activation. Sulfamethazine was negative in these tests, with the highest ineffective dose being 1000 μg/plate (1.0 mg/plate). Interactions Sixteen healthy volunteers participated in a crossover study examining the effect of ethanol on the acetylation rate of sulfadimidine (blood ethanol concentration approximately 1 g/L). In both rapid and slow acetylated individuals, ethanol treatment shortened the apparent half-life of the drug by approximately 20% (mean shortening of 39 ± 8 minutes), and increased the amount of drug acetylated in both blood and urine. In three slow acetylated individuals, the rate of acetylation in the blood was significantly increased after ethanol treatment, to the point that they would otherwise have been classified as rapid acetylated individuals. The acetylation rate of sulfadimidine increased by approximately 30% upon addition of ethanol (2 g/L) to isolated rat hepatocyte suspensions. A patient's usual alcohol consumption should be considered when assessing their acetylation status. Sulfonamides may interact with other drugs, including warfarin, methylamine, dapsone, and etodoxacin. They may enhance adverse reactions caused by methotrexate and pyrimethamine. Sulfonamides increase the metabolism of cyclosporine, leading to decreased plasma concentrations. Methylamine is metabolized to formaldehyde, which may form complexes with sulfonamides and precipitate. The use of sulfonamides in horses receiving detopromidine may cause arrhythmias. This precaution applies only to intravenously administered combination sulfonamides. /Sulfonamides/
The pharmacokinetic characteristics of sulfadiazine at a single intravenous injection and oral administration of 100 mg/kg body weight were investigated in clinically healthy (control) horses and horses receiving flunixin. Plasma sulfadiazine concentrations were determined by high-performance liquid chromatography (HPLC). All plasma sulfadiazine data after intravenous injection were best-fitted using a two-compartment open model employing sequential weighted nonlinear regression. Flunixin increased the rate of sulfadiazine return from peripheral tissues to the central compartment by 67% (K21), and K12 showed a trend towards an increase of 30%. The elimination half-life of sulfadiazine was shortened by 21%, the volume of distribution (Vdss) decreased by 18%, and the mean residence time (MRT) decreased by 20%. Following oral administration, both the control and flunixin groups showed rapid absorption of sulfadiazine, with absorption half-lives (t1/2 ab) of 0.5 h and 0.43 h, respectively. Peak plasma concentrations (Cmax) were 93.7 and 109 μg/mL, respectively, with times to peak concentration (tmax) of 2.36 h and 1.9 h, respectively. Horses pre-administered with flunixin showed a shorter elimination half-life (t1/2 ab) than the control group after oral administration. Following oral administration of 100 mg/kg body weight of sulfadiazine, the systemic bioavailability (F%) in the control group and horses treated with flunixin was 79.3% and 71.2%, respectively. Therefore, caution should be exercised when using sulfadiazine in horses concurrently treated with flunixin.

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Non-human toxicity values
Mouse intraperitoneal LD50: 1.06 g/kg

[1]. VAN Poucke LSG, et al. Pharmacokinetics and Tissue Residues of Sulfathiazole and Sulfamethazine in Pigs. J Food Prot. 1994 Sep;57(9):796-801.
[2]. Sheng Y J, et al. Production of chicken yolk IgY to sulfamethazine: comparison with rabbit antiserum IgG. Food and Agricultural Immunology. 2015, 26(3):305-316.

Sulfamethazine is an odorless, viscous, white or milky-white crystalline powder with a slightly bitter taste; it is an antibacterial drug. Sulfamethazine is a sulfonamide compound composed of a pyrimidine ring with methyl substituents at positions 4 and 6 and a 4-aminobenzenesulfonamide group at position 2. It has multiple functions, including anti-infective, carcinogenic, ligand, antibacterial, antimicrobial, EC 2.5.1.15 (dihydropterolate synthase) inhibitor, environmental pollutant, exogenous substance, and drug allergen. It belongs to the pyrimidine class of compounds and is a sulfonamide antibiotic, functionally related to sulfonamide compounds. It is a sulfonamide anti-infective drug. It has an antibacterial spectrum similar to other sulfonamide drugs. Sulfamethazine has been reported to be detected in Euglena gracilis, and relevant data are available. Sulfamethazine is a sulfonamide antibiotic used in animal husbandry. It is a sulfonamide anti-infective drug. It has a similar antibacterial spectrum to other sulfonamides.
See also: Sulfamethazine sodium (active ingredient); Sulfamethazine hydrogen sulfate (active ingredient); Chlortetracycline; Sulfamethazine (ingredient)...See more...
Drug Indications

For the treatment of bronchitis, prostatitis, and urinary tract infections caused by bacterial infections.
Mechanism of Action

Sulfonamides inhibit the enzymatic conversion of pteridine and PABA to dihydrofolate by competitively binding to dihydrofolate synthase (an intermediate in the synthesis of tetrahydrofolate (THF)) with para-aminobenzoic acid (PABA). THF is essential for the synthesis of purines and dTMP, and inhibiting its synthesis inhibits bacterial growth. Pyrimethamine and trimethoprim inhibit dihydrofolate reductase, another step in the synthesis of tetrahydrofolate, and therefore have a synergistic effect with sulfonamides.

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Therapeutic Use
Anti-infective Drugs
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private sources worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the title, description, and design of the study; participation requirements (eligibility criteria); the location where the study was conducted; contact information for the study location; and links to relevant information on other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Sulfamethazine is listed in the database.
Drug (Veterinary): Sulfamethazine is a broad-spectrum antimicrobial drug used to treat or prevent infections caused by susceptible microorganisms. Treatable infections include pneumonia, intestinal infections (especially coccidiosis), soft tissue infections, and urinary tract infections (UTI).
Medications (Veterinary): Sulfamethazine (also known as sulfadiazine) is widely used in veterinary medicine for pigs, often in combination with tetracycline and penicillin to maintain weight gain, promote growth, and improve feed conversion in pigs with atrophic rhinitis. Sulfamethazine is also effective against a variety of diseases in food animals. Common therapeutic uses in cattle include: treatment of bovine respiratory disease complex (transport fever complex); necrotizing foot dermatitis (hoof rot) and calf diphtheria; Escherichia coli infection (bacterial diarrhea); coccidiosis, acute mastitis, and acute metritis. Common therapeutic uses in sheep include: treatment of pasteurellosis; bacterial pneumonia; Escherichia coli infection (bacterial diarrhea); and control and treatment of coccidiosis. Common therapeutic uses in pigs include: treatment of bacterial pneumonia; swine Escherichia coli infection (bacterial diarrhea); bacterial swine enteritis; and reducing the incidence of neck abscesses. Common therapeutic uses in chickens include: control of infectious coryza; coccidiosis; acute fowl cholera; and pullorum disease. Common therapeutic uses of sulfadimidine in turkeys include: control of coccidiosis.
For more complete data on the therapeutic uses of sulfadimidine (7 types), please visit the HSDB record page.
Drug Warnings
Veterinarians: Adverse reactions to sulfonamides include allergic reactions, type II and III hypersensitivity reactions, arthritis, anemia, thrombocytopenia, liver disease, hypothyroidism (with long-term use), dry keratoconjunctivitis, and skin reactions. Canines may be more sensitive to sulfonamides than other animals because they lack the ability to acetylate sulfonamides into metabolites. Other, more toxic metabolites may persist. /Sulfonamides/
Veterinarians: Do not use in animals allergic to sulfonamides. Doberman Pinschers may be more sensitive to sulfonamides than other breeds. Use with caution in this breed. /Sulfonamides/

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Pharmacodynamics
Sulfamethazine is a sulfonamide drug that inhibits bacterial dihydrofolate synthesis by competitively binding to dihydrofolate synthase (dihydrofolate synthase) with para-aminobenzoic acid (PABA). Sulfamethazine has antibacterial activity. Inhibition of dihydrofolate synthesis reduces bacterial nucleotide and DNA synthesis.

C12H14N4O2S

278.33

278.083

57-68-1

Sulfamethazine sodium;1981-58-4;Sulfamethazine-d4;1020719-82-7;Sulfamethazine-13C6;77643-91-5

5327

Crystals from dioxane-water
Creamy-white powder or crystals from dioxan
White or yellowish-white powder

1.4±0.1 g/cm3

526.2±52.0 °C at 760 mmHg

197 °C

272.1±30.7 °C

0.0±1.4 mmHg at 25°C

1.644

0.8

2

6

3

19

377

0

S(C1C([H])=C([H])C(=C([H])C=1[H])N([H])[H])(N([H])C1=NC(C([H])([H])[H])=C([H])C(C([H])([H])[H])=N1)(=O)=O

ASWVTGNCAZCNNR-UHFFFAOYSA-N

InChI=1S/C12H14N4O2S/c1-8-7-9(2)15-12(14-8)16-19(17,18)11-5-3-10(13)4-6-11/h3-7H,13H2,1-2H3,(H,14,15,16)

4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide

HSDB 4157; HSDB 4157; HSDB 4157

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 (~359.29 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.98 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 (8.98 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 (8.98 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.)