Absorption, Distribution and Excretion
Following oral administration of Sulfisomidine, the average urinary recovery rate within 48 hours is 97%, of which 52% is intact drug and the remainder is N4-acetylated metabolites. This drug is secreted into human milk. After oral administration, Sulfisomidine is rapidly and completely absorbed; the small intestine is the primary site of absorption, but some drug may also be absorbed via the stomach. Sulfonamides exist in the blood in free, bound (acetylated and other possible bound forms), and protein-bound forms. The "free" form is considered the therapeutically active form. Approximately 85% of the Sulfisomidine dose is bound to plasma proteins, primarily albumin; 65% to 72% of the free fraction is in the non-acetylated form. Following a single oral dose of 2 g Sulfisomidine in healthy adult volunteers, the peak plasma concentration of intact Sulfisomidine ranged from 127 to 211 μg/mL (mean 169 μg/mL), with peak plasma concentrations occurring 1 to 4 hours (mean 2.5 hours). Following multiple oral doses of 500 mg (four times daily) in healthy volunteers, the mean steady-state plasma concentration of intact Sulfisomidine ranged from 49.9 to 88.8 μg/mL (mean 63.4 μg/mL). Following a single oral dose of 4 g acesulfame potassium in healthy volunteers, the peak plasma concentration of Sulfisomidine suspension in children ranged from 122 to 282 μg/mL (mean 181 μg/mL), with peak concentrations occurring 2 to 6 hours after administration. Even with the same dose of sulfonamides, plasma concentrations of acesulfame potassium can vary significantly. Monitoring of plasma concentrations is recommended for patients taking higher recommended doses of sulfonamides or undergoing treatment for serious infections. For most infections, a plasma concentration of 50 to 150 μg/mL for free sulfonamides is considered an effective therapeutic concentration, while for severe infections, the optimal concentration is between 120 and 150 μg/mL. The maximum plasma concentration of sulfonamides should not exceed 200 μg/mL, as the incidence of adverse reactions is higher above this concentration. For more complete data on the absorption, distribution, and excretion of Sulfisomidine (25 metabolites), please visit the HSDB record page. N1-AcetylSulfisomidine is metabolized in the gastrointestinal tract by digestive enzymes to Sulfisomidine, which is then absorbed in the form of Sulfisomidine. This enzymatic degradation is considered to be the reason for its slower absorption rate and lower peak plasma concentrations than those achieved after an equivalent oral dose of Sulfisomidine. With continued use of acetylSulfisomidine, its plasma concentration approaches that of Sulfisomidine. /Acesulfame K/
While the liver is the primary site of metabolism, sulfonamides can also be metabolized in other tissues. Most sulfonamides are primarily metabolized via N4-acetylation. The degree of acetylation varies over time, ranging from less than 5% for Sulfisomidine to as high as 40% for sulfadiazine. N4-acetylated metabolites are not antibacterial, have a higher affinity for plasma albumin compared to unacetylated drugs, and are generally less soluble than the parent sulfonamide, especially in acidic urine. Like acetylated derivatives, glucuronide derivatives are also not antibacterial; however, glucuronide derivatives are water-soluble, appear to have similar plasma binding capacity to unacetylated sulfonamides, and are not associated with adverse reactions. Sulfonamides
Identified sulfafuranzol urinary metabolites include acesulfame K, Sulfisomidine-N-glucuronide, Sulfisomidine-N-sulfonate, and sulfonamides. In humans, Sulfisomidine is primarily excreted in urine as the unchanged form (56%), N(4)-acetyl derivatives (18%), N(4)-glucuronide (3.4%), N(4)-sulfate (1.0%), and another glucuronide (possibly the N(2)-glucuronide of Sulfisomidine). The saturation metabolism (saturation first-pass metabolism) of Sulfisomidine N1-acetyl in rats following oral administration was investigated. A significant proportion of the total drug recovered in urine as N4-conjugates was observed after intravenous administration of acesulfame potassium or oral administration of the same dose. The elimination half-life after oral administration of Sulfisomidine ranged from 4.6 to 7.8 hours. Studies have shown that Sulfisomidine is eliminated more slowly in elderly subjects (63 to 75 years old) with impaired renal function (creatinine clearance of 37 to 68 mL/min). The plasma elimination half-life is 5.4 to 7.4 hours. The half-life of Sulfisomidine is approximately 6 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
For healthy, full-term infants, use of Sulfisomidine during lactation after the neonatal period appears to be acceptable. Until more data are accumulated, alternative medications may be used for infants with jaundice, illness, stress, or preterm birth due to the risk of bilirubin replacement and kernicterus. Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency should avoid Sulfisomidine during lactation. ◉ Effects on Breastfed Infants
No relevant published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No relevant published information found as of the revision date.

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Drug Interactions Sulfisomidine has been reported to potentially prolong prothrombin time in patients taking anticoagulants, including warfarin. When using Sulfisomidine in patients already receiving anticoagulation therapy, this interaction should be noted, and prothrombin time or other appropriate coagulation tests should be monitored. Studies have suggested that Sulfisomidine competes with thiopental sodium for plasma protein binding sites. A study involving 48 patients showed that intravenous Sulfisomidine reduced the amount of thiopental sodium required for anesthesia and shortened recovery time. It is currently unclear whether long-term oral Sulfisomidine has similar effects. Sulfonamides can displace methotrexate from plasma protein binding sites, thereby increasing the concentration of free methotrexate. Human studies have shown that infusion of Sulfisomidine can reduce plasma protein-bound methotrexate by one-quarter. Some sulfonamides can displace the protein binding sites of coumarin or indanedione anticoagulants, phenytoin anticonvulsants, or oral hypoglycemic agents, and/or inhibit their metabolism, leading to enhanced or prolonged effects and/or toxicity; dose adjustments may be necessary during and after sulfonamide treatment. /Sulfonamides/
For more complete data on interactions of Sulfisomidines (17 in total), please visit the HSDB record page.

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Non-human toxicity values
Rabbit oral LD50: 20000 mg/kg
Rabbit oral LD50: >1000 mg/kg body weight
Rats oral LD50: 10000 mg/kg
Mice oral LD50: 6800 mg/kg body weight

[1]. Identification of a new class of ETA selective endothelin antagonists by pharmacophore directed screening. Biochem Biophys Res Commun, 1994. 201(1): p. 228-34.

[2]. Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A. Nat Commun. 2019 Mar 27;10(1):1387.

[3]. Sulfisoxazole Elicits Robust Antitumour Immune Response Along with Immune Checkpoint Therapy by Inhibiting Exosomal PD-L1. Adv Sci (Weinh). 2022 Feb;9(5):e2103245.

[4]. Sulfisoxazole, an endothelin receptor antagonist, protects retinal neurones from insults of ischemia/reperfusion or lipopolysaccharide. Neurochem Int. 2006 Jun;48(8):708-17.

Sulfisomidine is an odorless white to pale yellow crystalline powder with a slightly bitter taste and an acidic reaction to litmus paper. (NTP, 1992)
Sulfisomidine is a sulfonamide antibacterial drug containing an oxazole substituent in its molecular structure. It has antibacterial activity against a variety of Gram-negative and Gram-positive bacteria. It is both an antibacterial drug and a drug allergen. It belongs to the isoxazole, sulfonamide, and sulfonamide antibiotic classes. Its function is related to sulfonamide drugs.
Sulfisomidine is a short-acting sulfonamide antibacterial drug, active against a variety of Gram-negative and Gram-positive bacteria.
Sulfisomidine is a sulfonamide antibacterial drug.
Sulfisomidine is a broad-spectrum, short-acting sulfonamide drug and a synthetic analog of para-aminobenzoic acid (PABA), possessing antibacterial activity. Sulfisomidine competes with para-aminobenzoic acid (PABA) for the bacterial enzyme dihydropteroate synthase, thereby preventing PABA from being incorporated into dihydrofolate (a direct precursor of folic acid). This leads to inhibition of bacterial folic acid synthesis as well as de novo synthesis of purines and pyrimidines, ultimately resulting in cell growth arrest and cell death. A short-acting sulfonamide antibacterial drug, active against a variety of Gram-negative and Gram-positive bacteria. See also: acesulfame potassium (its active fraction); Sulfisomidine sodium (its active fraction); phenapyridine hydrochloride; Sulfisomidine (component)...see more...

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Drug Indications
For the treatment of severe, recurrent, or prolonged urinary tract infections, meningococcal meningitis, acute otitis media, trachoma, inclusion conjunctivitis, nocardiosis, chancroid, toxoplasmosis, malaria, and other bacterial infections.

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Mechanism of Action
Sulfisomidine is a competitive inhibitor of dihydropteridine synthase. It inhibits bacterial synthesis of dihydrofolate by preventing the condensation reaction between pteridine and p-aminobenzoic acid (PABA), a substrate of dihydropteridine synthase. This inhibited reaction is essential for folic acid synthesis in these microorganisms.
Sulfonamides are bacteriostatic agents, and all sulfonamides have similar antibacterial spectra. Sulfonamides inhibit bacterial synthesis of dihydrofolate by competitively inhibiting dihydropteridine synthase, preventing the condensation reaction between pteridine and aminobenzoic acid. Resistant strains have altered dihydropteridine synthase, exhibiting reduced affinity for sulfonamides or producing more aminobenzoic acid. Sulfonamides generally have bacteriostatic activity. Sulfonamides interfere with the utilization of p-aminobenzoic acid (PABA) in susceptible bacteria, thereby inhibiting its activity in the biosynthesis of tetrahydrofolate (the reduced form of folic acid). Sulfonamides are structural analogues of PABA, and they appear to interfere with PABA utilization by competitively inhibiting dihydropteranoic acid synthase. Dihydropteranoic acid synthase catalyzes the synthesis of dihydropteranoic acid (a precursor to tetrahydrofolate) from PABA and pteridine; however, other mechanisms affecting the biosynthetic pathway may also exist. Compounds such as pyrimidine methylamine and trimethoprim can block later stages of folic acid synthesis and synergize with sulfonamides. Sulfonamides only inhibit microorganisms capable of synthesizing folic acid themselves; animal cells and bacteria capable of utilizing folic acid precursors or already synthesizing folic acid are unaffected by these drugs. The antibacterial activity of sulfonamides has been reported to decrease in the presence of blood or purulent exudates. /Sulfonamides/

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Therapeutic Use
Anti-infectives/SRP: Antibacterial Agents/
Acute, recurrent, or chronic urinary tract infections (primarily pyelonephritis, pyelonephritis, and cystitis) caused by susceptible bacteria (usually Escherichia coli, Klebsiella pneumoniae-Enterobacter spp., Staphylococcus, Proteus mirabilis, and less commonly Proteus vulgaris) without obstructive urinary tract disease or foreign bodies. /US Product Label Includes/
Meningococcal meningitis proven susceptible to this product. Haemophilus influenzae meningitis, may be used as adjunctive therapy with parenteral streptomycin. /US Product Label Includes/
Can be used to prevent meningococcal meningitis when Group A strains known to be susceptible to sulfonamides are prevalent in households or large closed populations. (The prophylactic effect of sulfonamides has not been proven when Group B or C infections are prevalent, and may be harmful in closed populations.) Important: In vitro sulfonamide susceptibility testing is not always reliable. This test must be carefully combined with bacteriological and clinical responses. When the patient has already taken sulfonamides, subsequent cultures should be supplemented with aminobenzoic acid. /US product label contains/
For more complete data on the therapeutic uses of sulfisoxazole (of 26 types), please visit the HSDB record page.

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Drug Warnings
Sulfisomidine is contraindicated in the following patient groups: patients with known hypersensitivity to sulfonamides; infants under 2 months of age (except as adjunctive therapy to pyrimethamine in the treatment of congenital toxoplasmosis); women of term pregnancy; and mothers of infants under 2 months of age who are breastfeeding.
Sulfonamides are contraindicated in women of term pregnancy, infants under 2 months of age, and mothers of infants under 2 months of age who are breastfeeding, as sulfonamides may cause neonatal kernicterus by displacing bilirubin in plasma proteins.
Although rare, death can still occur after taking sulfonamides due to serious adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood disorders.
Sulfonamides, including Sulfisomidine, should be discontinued immediately if a rash or any signs of adverse reactions appear.
For more complete data on drug warnings for Sulfisomidine (34 in total), please visit the HSDB record page.

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Pharmacodynamics
Sulfisomidine is a sulfonamide antibiotic. Sulfonamides are synthetic antibacterial antibiotics with broad-spectrum antibacterial activity against most Gram-positive bacteria and many Gram-negative bacteria. However, many strains of the same species may develop resistance to them. Sulfonamides inhibit bacterial growth by competitively inhibiting para-aminobenzoic acid in the folate metabolic cycle. Bacteria exhibit similar sensitivity to various sulfonamides; resistance to one sulfonamide implies resistance to all sulfonamides. Most sulfonamides are well absorbed orally. However, parenteral administration is challenging due to the strong alkalinity and tissue irritation of soluble sulfonamide salts. Sulfonamides are widely distributed in all tissues. High concentrations can be reached in pleural fluid, peritoneal fluid, synovial fluid, and ocular fluid. Although these drugs are no longer used to treat meningitis, high concentrations remain in the cerebrospinal fluid of patients with meningeal infections. Pus can inhibit their antibacterial activity.

C11H13N3O3S

267.303

267.067

127-69-5

Sulfisoxazole diethanolamine;4299-60-9

5344

Colorless prisms
White to slightly yellowish crystalline powder

1.4±0.1 g/cm3

482.2±55.0 °C at 760 mmHg

195°C

245.4±31.5 °C

0.0±1.2 mmHg at 25°C

1.626

1.01

2

6

3

18

374

0

S(C1C([H])=C([H])C(=C([H])C=1[H])N([H])[H])(N([H])C1=C(C([H])([H])[H])C(C([H])([H])[H])=NO1)(=O)=O

NHUHCSRWZMLRLA-UHFFFAOYSA-N

InChI=1S/C11H13N3O3S/c1-7-8(2)13-17-11(7)14-18(15,16)10-5-3-9(12)4-6-10/h3-6,14H,12H2,1-2H3

4-amino-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide

NU 445; NU-445; NU445

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 : ≥ 150 mg/mL (~561.17 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.35 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 (9.35 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 (9.35 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.)