Absorption, Distribution and Excretion
The mean urinary excretion recovery following oral administration of sulfisoxazole is 97% within 48 hours, of which 52% is intact drug, with the remaining as the N4-acetylated metabolite. It is excreted in human milk.
Following oral administration, sulfisoxazole is rapidly and completely absorbed; the small intestine is the major site of absorption, but some of the drug is absorbed from the stomach. Sulfonamides are present in the blood as free, conjugated (acetylated and possibly other forms) and protein-bound forms. The amount present as "free" drug is considered to be the therapeutically active form. Approximately 85% of a dose of sulfisoxazole is bound to plasma proteins, primarily to albumin; 65% to 72% of the unbound portion is in the nonacetylated form.
Maximum plasma concentrations of intact sulfisoxazole following a single 2-g oral dose of sulfisoxazole to healthy adult volunteers ranged from 127 to 211 ug/mL (mean, 169 ug/mL) and the time of peak plasma concentration ranged from 1 to 4 hours (mean, 2.5 hours). ... After multiple-dose oral administration of 500 mg /four times a day/ to healthy volunteers, the average steady-state plasma concentrations of intact sulfisoxazole ranged from 49.9 to 88.8 ug/mL (mean, 63.4 ug/mL).
Following a single 4-g dose of acetyl sulfisoxazole to healthy volunteers, maximum plasma concentrations of sulfisoxazole ranged from 122 to 282 ug/mL (mean, 181 ug/mL) for the pediatric suspension and occurred between 2 and 6 hours postadministration. /Acetyl-sulfisoxazole/
Wide variation in blood levels may result following identical doses of a sulfonamide. Blood levels should be measured in patients receiving sulfonamides at the higher recommended doses or being treated for serious infections. Free sulfonamide blood levels of 50 to 150 ug/mL may be considered therapeutically effective for most infections, with blood levels of 120 to 150 ug/mL being optimal for serious infections. The maximum sulfonamide level should not exceed 200 ug/mL, since adverse reactions occur more frequently above this concentration.
For more Absorption, Distribution and Excretion (Complete) data for SULFISOXAZOLE (25 total), please visit the HSDB record page.

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Metabolism / Metabolites
N1-acetyl sulfisoxazole is metabolized to sulfisoxazole by digestive enzymes in the gastrointestinal tract and is absorbed as sulfisoxazole. This enzymatic splitting is presumed to be responsible for slower absorption and lower peak blood concentrations than are attained following administration of an equal oral dose of sulfisoxazole. With continued administration of acetyl sulfisoxazole, blood concentrations approximate those of sulfisoxazole. /Acetyl-sulfisoxazole/
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/
Identified urinary metabolites of sulfafurazole are acetylsulphisoxazole, sulphisoxazole-N-glucuronide, sulphisoxazole-N-sulphonate and sulphanilamide.
In man it is excreted in urine as unchanged sulfisoxazole (56%), N(4)-acetyl derivative (18%), N(4)-glucuronide (3.4%), N(4)-sulfate (1.0%) & a second glucuronide which is probably N(2)-glucuronide of sulfisoxazole.
Saturable metabolism of sulfisoxazole N1-acetyl in the rat during the initial pass of the drug from the intestinal lumen through the liver following oral administration of the drug (saturable first-pass metabolism) was investigated. The fraction of the total amount of drug recovered from the urine as the N4-conjugate fraction was apparent following the intravenous administration of sulfisoxazole acetyl or the oral administration of sulfisoxazole at the same dose levels.

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Biological Half-Life
The elimination half-life of sulfisoxazole ranged from 4.6 to 7.8 hours after oral administration. The elimination of sulfisoxazole has been shown to be slower in elderly subjects (63 to 75 years) with diminished renal function (creatinine clearance, 37 to 68 mL/min).
The half-life of elimination from plasma ranged from 5.4 to 7.4 hr. /Acetyl-sulfisoxazole/
The half-life of sulfafurazole is approximately 6 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
With healthy, fullterm infants it appears acceptable to use sulfisoxazole during breastfeeding after the newborn period. Until further data are accumulated, alternate agents should probably be used in jaundiced, ill, stressed or premature infants, because of the risk of bilirubin displacement and kernicterus. Sulfisoxazole should be avoided while breastfeeding a glucose-6-phosphate dehydrogenase (G6PD) deficient infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
It has been reported that sulfisoxazole may prolong the prothrombin time in patients who are receiving anticoagulants, including warfarin. This interaction should be kept in mind when /sulfisoxazole/ is given to patients already on anticoagulant therapy, and prothrombin time or other suitable coagulation test should be monitored.
It has been proposed that sulfisoxazole competes with thiopental for plasma protein binding. In one study involving 48 patients, intravenous sulfisoxazole resulted in a decrease in the amount of thiopental required for anesthesia and in a shortening of the awakening time. It is not known whether chronic oral doses of sulfisoxazole would have a similar effect.
Sulfonamides can displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. Studies in man have shown sulfisoxazole infusions to decrease plasma protein-bound methotrexate by one-fourth.
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/
For more Interactions (Complete) data for SULFISOXAZOLE (17 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rabbit oral 20000 mg/kg
LD50 Rabbit oral >1000 mg/kg bw
LD50 Rat oral 10000 mg/kg
LD50 Mice oral 6800 mg/kg bw

[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.

Sulfisoxazole is an odorless white to yellowish crystalline powder. Slightly bitter taste. Acid to litmus. (NTP, 1992)
Sulfisoxazole is a sulfonamide antibacterial with an oxazole substituent. It has antibiotic activity against a wide range of gram-negative and gram-positive organisms. It has a role as an antibacterial drug and a drug allergen. It is a member of isoxazoles, a sulfonamide and a sulfonamide antibiotic. It is functionally related to a sulfanilamide.
A short-acting sulfonamide antibacterial with activity against a wide range of gram- negative and gram-positive organisms.
Sulfisoxazole is a Sulfonamide Antimicrobial.
Sulfisoxazole is a broad-spectrum, short-acting sulfanilamide and a synthetic analog of para-aminobenzoic acid (PABA) with antibacterial property. Sulfisoxazole competes with PABA for the bacterial enzyme dihydropteroate synthase, thereby preventing the incorporation of PABA into dihydrofolic acid, the immediate precursor of folic acid. This leads to an inhibition of bacterial folic acid synthesis and de novo synthesis of purines and pyrimidines, ultimately resulting in cell growth arrest and cell death.
A short-acting sulfonamide antibacterial with activity against a wide range of gram- negative and gram-positive organisms.
See also: Sulfisoxazole Acetyl (is active moiety of); Sulfisoxazole sodium (is active moiety of); Phenazopyridine hydrochloride; sulfisoxazole (component of) ... View More ...

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Drug Indication
For the treatment of severe, repeated, or long-lasting 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
Sulfisoxazole is a competitive inhibitor of the enzyme dihydropteroate synthetase. It inhibits bacterial synthesis of dihydrofolic acid by preventing the condensation of the pteridine with para-aminobenzoic acid (PABA), a substrate of the enzyme dihydropteroate synthetase. The inhibited reaction is necessary in these organisms for the synthesis of folic acid.
The sulfonamides are bacteriostatic agents and the spectrum of activity is similar for all. Sulfonamides inhibit bacterial synthesis of dihydrofolic acid by preventing the condensation of the pteridine with aminobenzoic acid through competitive inhibition of the enzyme dihydropteroate synthetase. Resistant strains have altered dihydropteroate synthetase with reduced affinity for sulfonamides or produce increased quantities of aminobenzoic 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/

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Therapeutic Uses
Anti-Infective Agents /SRP: Antibacterial/
Acute, recurrent or chronic urinary tract infections (primarily pyelonephritis, pyelitis and cystitis) due to susceptible organisms (usually Escherichia coli, Klebsiella-Enterobacter, staphylococcus, Proteus mirabilis and, less frequently, Proteus vulgaris) in the absence of obstructive uropathy or foreign bodies. /Included in US product label/
Meningococcal meningitis where the organism has been demonstrated to be susceptible. Haemophilus influenzae meningitis as adjunctive therapy with parenteral streptomycin. /Included in US product label/
Meningococcal meningitis prophylaxis when sulfonamide-sensitive group A strains are known to prevail in family groups or larger closed populations. (The prophylactic usefulness of sulfonamides when group B or C infections are prevalent has not been proven and in closed population groups may be harmful.) Important Note: In vitro sulfonamide susceptibility tests are not always reliable. The test must be carefully coordinated with bacteriologic and clinical response. When the patient is already taking sulfonamides, follow-up cultures should have aminobenzoic acid added to the culture media. /Included in US product label/
For more Therapeutic Uses (Complete) data for SULFISOXAZOLE (26 total), please visit the HSDB record page.

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Drug Warnings
/Sulfisoxazole/ is contraindicated in the following patient populations: patients with a known hypersensitivity to sulfonamides; infants less than 2 months of age (except in the treatment of congenital toxoplasmosis as adjunctive therapy with pyrimethamine); pregnant women at term; and mothers nursing infants less than 2 months of age.
Use in pregnant women at term, in infants less than 2 months of age and in mothers nursing infants less than 2 months of age is contraindicated because sulfonamides may promote kernicterus in the newborn by displacing bilirubin from plasma proteins.
Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.
Sulfonamides, including sulfisoxazole, should be discontinued at the first appearance of skin rash or any sign of an adverse reaction.
For more Drug Warnings (Complete) data for SULFISOXAZOLE (34 total), please visit the HSDB record page.

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Pharmacodynamics
Sulfisoxazole 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 p-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.

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.)