Identification

Name
Acetyl sulfisoxazole
Accession Number
DB14033  (DBSALT000856)
Type
Small Molecule
Groups
Approved, Vet approved
Description

Sulfisoxazole acetyl is an ester of sulfisoxazole, a broad-spectrum sulfanilamide and a synthetic analog of para-aminobenzoic acid (PABA) with antibacterial activity. Sulfisoxazole acetyl competes with PABA for the bacterial enzyme, dihydropteroate synthase, preventing the incorporation of PABA into dihydrofolic acid, which is the precursor of folic acid. This process causes an inhibition of bacterial folic acid synthesis and de novo synthesis of purines and pyrimidines, resulting in cell growth arrest and cell death [2].

It is often combined with erythromycin to treat acute otitis media caused by the bacteria, haemophilus influenzae [3].

Structure
Thumb
Synonyms
  • Sulfisoxazole acetyl
Active Moieties
NameKindUNIICASInChI Key
Sulfisoxazoleunknown740T4C525W127-69-5NHUHCSRWZMLRLA-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GantrisinSuspension0.5 g/5mLOralGenentech, Inc.1953-12-042011-07-08Us
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Erythromycin Ethylsuccinate and Sulfisoxazole AcetylAcetyl sulfisoxazole (600 mg/5mL) + Erythromycin ethylsuccinate (200 mg/5mL)Granule, for suspensionOralPhysicians Total Care, Inc.2000-10-11Not applicableUs
Erythromycin Ethylsuccinate and Sulfisoxazole AcetylAcetyl sulfisoxazole (600 mg/5mL) + Erythromycin ethylsuccinate (200 mg/5mL)Granule, for suspensionOralPhysicians Total Care, Inc.1995-02-012011-04-30Us
Erythromycin Ethylsuccinate and Sulfisoxazole AcetylAcetyl sulfisoxazole (600 mg/5mL) + Erythromycin ethylsuccinate (200 mg/5mL)Granule, for suspensionOralRebel Distributors1988-05-20Not applicableUs
Erythromycin Ethylsuccinate and Sulfisoxazole AcetylAcetyl sulfisoxazole (600 mg/5mL) + Erythromycin ethylsuccinate (200 mg/5mL)Granule, for suspensionOralTeva Women's Health1998-06-012014-11-30Us
Categories
UNII
WBT5QH3KED
CAS number
80-74-0
Weight
Average: 309.34
Monoisotopic: 309.078327149
Chemical Formula
C13H15N3O4S
InChI Key
JFNWFXVFBDDWCX-UHFFFAOYSA-N
InChI
InChI=1S/C13H15N3O4S/c1-8-9(2)15-20-13(8)16(10(3)17)21(18,19)12-6-4-11(14)5-7-12/h4-7H,14H2,1-3H3
IUPAC Name
N-(4-aminobenzenesulfonyl)-N-(3,4-dimethyl-1,2-oxazol-5-yl)acetamide
SMILES
CC(=O)N(C1=C(C)C(C)=NO1)S(=O)(=O)C1=CC=C(N)C=C1

Pharmacology

Indication

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 [9]

Meningococcal meningitis where the organism has been demonstrated to be susceptible. Haemophilus influenzae meningitis as adjunctive therapy with parenteral streptomycin [9]

Meningococcal meningitis prophylaxis [9].

Acute otitis media due to Haemophilus influenzae when used concomitantly with adequate doses of penicillin or erythromycin (see appropriate labeling for prescribing information) [9].

Trachoma, inclusion conjunctivitis, nocardiosis, chancroid, toxoplasmosis as adjunctive therapy with pyrimethamine. Malaria due to chloroquine-resistant strains of Plasmodium falciparum, when used as adjunctive therapy [9].

Currently, the increasing frequency of resistant organisms is a limitation of the usefulness of antibacterial agents including the sulfonamides, especially in the treatment of chronic and recurrent urinary tract infections [9].

Associated Conditions
Pharmacodynamics

Sulfisoxazole is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with action against most gram-positive and many gram-negative organisms. Many strains of an individual species may be resistant to this drugf. Sulfonamides inhibit the 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. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus [6].

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 [6].

TargetActionsOrganism
ADihydropteroate synthase
inhibitor
Escherichia coli (strain K12)
Absorption

Readily absorbed from the gastrointestinal tract [5].

In a pharmacokinetic study, the adjustments for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95 +/- 0.04 [7].

Volume of distribution

The sulfonamides are widely distributed throughout all body tissues [5].

It readily crosses the placental barrier and enters into fetal circulation and also crosses the blood-brain barrier. In healthy subjects, cerebrospinal fluid concentrations of sulfisoxazole vary; in patients with meningitis, however, concentrations of free drug in cerebrospinal fluid as high as 94 mcg/mL have been reported [9].

In a pharmacokinetic study, the apparent volume of distribution for total drug was 10.9 +/- 2.0 liters and 136 +/- 36 liters for the unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly [7].

Protein binding

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 [9].

Metabolism

Sulfisoxazole acetyl is a prodrug of sulfisoxazole. The acetyl group is added to make the drug poorly water-soluble and is hydrolyzed in vivo to the active drug [9], [11].

N1-acetyl sulfisoxazole is metabolized to sulfisoxazole by digestive enzymes in the gastrointestinal tract and is absorbed as sulfisoxazole. This enzymatic splitting is thought to be responsible for slower absorption and lower peak blood concentrations are achieved after administration of an equal oral dose of sulfisoxazole. With sustained administration of acetyl sulfisoxazole, blood concentrations approximate those of sulfisoxazole. Following a single 4 gram dose of acetyl sulfisoxazole to healthy volunteers, maximum plasma concentrations of sulfisoxazole ranged from 122 to 282 mcg/mL (mean, 181 mcg/mL) for the pediatric suspension and occurred between 2 and 6 hours postadministration of sulfisoxazole, in a pharmacokinetic study [9].

Route of elimination

The mean urinary excretion recovery following oral administration of sulfisoxazole is 97% within 48 hours, of which 52% is the parent drug, and the remaining as the N4-acetylated metabolite. It is excreted in human milk [5].

Sulfisoxazole and its acetylated metabolites are excreted primarily by the kidneys through glomerular filtration [9].

Half life

The serum half-life is 10 -12 hours [5].

Clearance

The clearance of sulfisoxazole is 18.7 +/- 3.9 ml/min for total drug and 232 +/- 64 ml/min for the unbound drug [7].

Toxicity

LD50=6800 mg/kg (Orally in mice) [10].

Sulfonamide-induced hypersensitivity reactions, although uncommon, can be severe. They can include rare life-threatening cutaneous reactions such as erythema multiform (Stevens-Johnson syndrome) and toxic epidermal necrolysis. Crystalluria may result in dysuria, renal colic, haematuria and acute renal obstruction [8].

Other infrequent reactions include granulocytopenia, agranulocytosis, aplastic anemia, thrombocytopenic purpura and toxic hepatitis. Rarely, hemolysis may occur in individuals deficient in glucose-6-phosphate dehydrogenase [8].

The severe or irreversible adverse effects of sulfisoxazole, which give rise to more complications which may include: nephrotoxicity, blood dyscrasias, interstitial nephritis, hematuria, crystalluria, oliguria, anuria, lumbar pain, and tubular necrosis [8].

The symptomatic adverse reactions produced by sulfisoxazole are more or less tolerable and if severe, may be treated symptomatically, these include anorexia, diarrhea, rashes, pruritus, nausea and vomiting, hypersensitivity reactions, Photosensitivity reactions [5].

Overdosage: Continuously forced diuresis may be beneficial and an alkaline urine should be initiated [5].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Acetyl sulfisoxazole is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Acetyl sulfisoxazole is combined with (S)-Warfarin.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be increased when used in combination with Acetyl sulfisoxazole.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Acetyl sulfisoxazole is combined with 4-hydroxycoumarin.
AcarboseThe therapeutic efficacy of Acarbose can be increased when used in combination with Acetyl sulfisoxazole.
AceclofenacThe metabolism of Aceclofenac can be decreased when combined with Acetyl sulfisoxazole.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Acetyl sulfisoxazole.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Acetyl sulfisoxazole.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acidThe metabolism of Acetylsalicylic acid can be decreased when combined with Acetyl sulfisoxazole.
Food Interactions
Not Available

References

General References
  1. Suber RL, Lee C, Torosian G, Edds GT: Pharmacokinetics of sulfisoxazole compared in humans and two monogastric animal species. J Pharm Sci. 1981 Sep;70(9):981-4. [PubMed:6101167]
  2. Acetyl Sulfisoxazole [Link]
  3. ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL [Link]
  4. Sulfisoxazole [Link]
  5. Sulfadiazine or Sulfisoxazole [Link]
  6. Sulfisoxazole [Link]
  7. Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing [Link]
  8. Gantrisin [Link]
  9. Gantrisin Description [Link]
  10. Sulfisoxazole, ToxNET [Link]
  11. Sulfisoxazole [Link]
External Links
PubChem Compound
6662
ChemSpider
6410
ChEBI
135975
ChEMBL
CHEMBL1200910
ATC Codes
G01AE10 — Combinations of sulfonamides
MSDS
Download (200 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Granule, for suspensionOral
SuspensionOral0.5 g/5mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)192 - 195 MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.136 mg/mLALOGPS
logP1.02ALOGPS
logP0.72ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)18.1ChemAxon
pKa (Strongest Basic)1.61ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.5 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity77.48 m3·mol-1ChemAxon
Polarizability30.24 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminobenzenesulfonamides. These are organic compounds containing a benzenesulfonamide moiety with an amine group attached to the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzenesulfonamides
Direct Parent
Aminobenzenesulfonamides
Alternative Parents
Benzenesulfonyl compounds / Aniline and substituted anilines / Organosulfonic acids and derivatives / Isoxazoles / Heteroaromatic compounds / Aminosulfonyl compounds / Acetamides / Amino acids and derivatives / Oxacyclic compounds / Azacyclic compounds
show 5 more
Substituents
Aminobenzenesulfonamide / Benzenesulfonyl group / Aniline or substituted anilines / Azole / Isoxazole / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Sulfonyl / Aminosulfonyl compound / Acetamide
show 18 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.
Gene Name
folP
Uniprot ID
P0AC13
Uniprot Name
Dihydropteroate synthase
Molecular Weight
30614.855 Da
References
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  2. Jorgensen JH, Crawford SA, Fiebelkorn KR: Susceptibility of Neisseria meningitidis to 16 antimicrobial agents and characterization of resistance mechanisms affecting some agents. J Clin Microbiol. 2005 Jul;43(7):3162-71. [PubMed:16000430]
  3. Fiebelkorn KR, Crawford SA, Jorgensen JH: Mutations in folP associated with elevated sulfonamide MICs for Neisseria meningitidis clinical isolates from five continents. Antimicrob Agents Chemother. 2005 Feb;49(2):536-40. [PubMed:15673729]
  4. Hong YL, Hossler PA, Calhoun DH, Meshnick SR: Inhibition of recombinant Pneumocystis carinii dihydropteroate synthetase by sulfa drugs. Antimicrob Agents Chemother. 1995 Aug;39(8):1756-63. [PubMed:7486915]
  5. Sulfisoxazole [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Komatsu K, Ito K, Nakajima Y, Kanamitsu Si, Imaoka S, Funae Y, Green CE, Tyson CA, Shimada N, Sugiyama Y: Prediction of in vivo drug-drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments. Drug Metab Dispos. 2000 Apr;28(4):475-81. [PubMed:10725317]

Drug created on May 17, 2018 11:14 / Updated on November 02, 2018 07:49