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Identification
NameNitazoxanide
Accession NumberDB00507  (APRD00558)
Typesmall molecule
Groupsapproved, investigational
Description

Nitazoxanide, also known by the brand name Alinia, is a synthetic nitrothiazolyl-salicylamide derivative and an anti-protozoal agent. It is approved for treatment of infectious diarrhea caused by Cryptosporidium parvum and Giardia lamblia in patients 1 year of age and older. Following oral administration it is rapidly hydrolyzed to its active metabolite, tizoxanide, which is 99% protein bound. Peak concentrations are observed 1–4 hours after administration. It is excreted in the urine, bile and feces. Untoward effects include abdominal pain, vomiting and diarrhea. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
AdrovetNot AvailableIS
NitaxozanidGermanINN
NitaxozanideFrenchINN
NitazoxanidaSpanishINN
NitazoxanidumLatinINN
NodikNot AvailableIS
OmniparaxNot AvailableIS
SaltsNot Available
Brand names
NameCompany
AliniaRomark
Alpex NizoxAlpex Pharmaceutical
ANNITAAlpex Pharmaceutical
AzoxanidG&R
CelectanFarma
ColufaseRoemmers
ColuquimQuilab
DaxonSiegfried
DianideGeneral Pharma
DiarACI
FamidoxLafrancol
KasideLafrancol
KazideLafrancol
LarvisolArmofar
LumbrisFarmedic
MixelCalifornia
NiazidApex
NitaxDelta
NitaxideBeximco
NitazetGlenmark
NitazofinBussié
Brand mixtures
Brand NameIngredients
Armbid-NTNitazoxanide and Ofloxacin
Bacter-NZNitazoxanide and Ofloxacin
FlagynorNitazoxanide and Ofloxacin
Inflobid-NXTNitazoxanide and Ofloxacin
Nitazet-ONitazoxanide and Ofloxacin
Nitzix-ONitazoxanide and Ofloxacin
Nizonide-ONitazoxanide and Ofloxacin
Categories
CAS number55981-09-4
WeightAverage: 307.282
Monoisotopic: 307.026291103
Chemical FormulaC12H9N3O5S
InChI KeyYQNQNVDNTFHQSW-UHFFFAOYSA-N
InChI
InChI=1S/C12H9N3O5S/c1-7(16)20-9-5-3-2-4-8(9)11(17)14-12-13-6-10(21-12)15(18)19/h2-6H,1H3,(H,13,14,17)
IUPAC Name
2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl acetate
SMILES
CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C(S1)[N+]([O-])=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenol Esters
Direct parentPhenol Esters
Alternative parentsSalicylamides; Benzamides; Benzoyl Derivatives; Nitrothiazoles; Phenol Ethers; 2,5-disubstituted Thiazoles; Alkyl Aryl Ethers; Aminothiazoles; Nitro Compounds; Secondary Carboxylic Acid Amides; Carboxylic Acid Esters; Nitronic Acids; Enolates; Organic Oxoazanium Compounds; Polyamines; Carboxylic Acids
Substituentsphenol ether; nitrothiazole; benzoyl; 2,5-disubstituted 1,3-thiazole; alkyl aryl ether; 1,3-thiazolamine; thiazole; azole; carboxamide group; nitro compound; nitronic acid; secondary carboxylic acid amide; carboxylic acid ester; polyamine; organic oxoazanium; ether; carboxylic acid; enolate; carboxylic acid derivative; organonitrogen compound; amine
Classification descriptionThis compound belongs to the phenol esters. These are aromatic compounds containing a benzene ring substituted by an hydroxyl group and an ester group.
Pharmacology
IndicationFor the treatment of diarrhea in adults and children caused by the protozoa Giardia lamblia and for the treatment of diarrhea in children caused by the protozoa Cryptosporidium parvum.
PharmacodynamicsNitazoxanide is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that nitazoxanide inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Nitazoxanide is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, nitazoxanide is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Mechanism of actionThe antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from Giardia lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of Giardia lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity.
AbsorptionThe relative bioavailability of the suspension compared to the tablet was 70%. When administered with food the AUC and Cmax increased by two-fold and 50%, respectively, for the tablet and 45 to 50% and ≤ 10%, respectively, for the oral suspension.
Volume of distributionNot Available
Protein bindingVery High (greater than 99%), bound to proteins. Binding is not affected by degree of renal impairment.
Metabolism

Rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide), followed by conjugation, primarily by glucuronidation to tizoxanide glucuronide.

SubstrateEnzymesProduct
Nitazoxanide
Not Available
Desacetyl-nitazoxanideDetails
Nitazoxanide
Not Available
Tizoxanide glucuronideDetails
Route of eliminationTizoxanide is excreted in the urine, bile and feces, and tizoxanide glucuronide is excreted in urine and bile. Approximately two-thirds of the oral dose of nitazoxanide is excreted in the feces and one-third in the urine.
Half life3.5 hours in patients with normal renal function
ClearanceNot Available
ToxicityIn acute studies in rodents and dogs, the oral LD50 was higher than 10,000 mg/kg. Single oral doses of up to 4000 mg nitazoxanide have been administered to healthy adult volunteers without significant adverse effects.
Affected organisms
  • Protozoa
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9045
Blood Brain Barrier + 0.7175
Caco-2 permeable - 0.5571
P-glycoprotein substrate Non-substrate 0.7978
P-glycoprotein inhibitor I Non-inhibitor 0.8874
P-glycoprotein inhibitor II Non-inhibitor 0.9836
Renal organic cation transporter Non-inhibitor 0.9228
CYP450 2C9 substrate Non-substrate 0.7438
CYP450 2D6 substrate Non-substrate 0.8431
CYP450 3A4 substrate Non-substrate 0.5596
CYP450 1A2 substrate Non-inhibitor 0.6339
CYP450 2C9 substrate Inhibitor 0.6655
CYP450 2D6 substrate Non-inhibitor 0.9027
CYP450 2C19 substrate Non-inhibitor 0.6341
CYP450 3A4 substrate Inhibitor 0.6669
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5635
Ames test AMES toxic 0.8322
Carcinogenicity Non-carcinogens 0.7746
Biodegradation Ready biodegradable 0.5458
Rat acute toxicity 1.7902 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9283
hERG inhibition (predictor II) Non-inhibitor 0.9295
Pharmacoeconomics
Manufacturers
  • Romark laboratories
Packagers
Dosage forms
FormRouteStrength
SuspensionOral
TabletOral
Prices
Unit descriptionCostUnit
Alinia 500 mg tablet23.22USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States59655901997-07-032017-07-03
United States53875981995-02-072012-02-07
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point202 °CNot Available
logP1.2Not Available
Predicted Properties
PropertyValueSource
water solubility7.55e-03 g/lALOGPS
logP2.14ALOGPS
logP2.12ChemAxon
logS-4.6ALOGPS
pKa (strongest acidic)8.3ChemAxon
pKa (strongest basic)-4.2ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count1ChemAxon
polar surface area114.11ChemAxon
rotatable bond count5ChemAxon
refractivity73.89ChemAxon
polarizability27.54ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US3950351
General Reference
  1. Parasitic infections. Am J Transplant. 2004 Nov;4 Suppl 10:142-55. Pubmed
External Links
ResourceLink
KEGG DrugD02486
PubChem Compound41684
PubChem Substance46507813
ChemSpider38037
BindingDB50182652
Therapeutic Targets DatabaseDAP001293
PharmGKBPA164754874
RxListhttp://www.rxlist.com/cgi/generic/alinia.htm
Drugs.comhttp://www.drugs.com/cdi/nitazoxanide.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ali1659.shtml
WikipediaNitazoxanide
ATC CodesP01AX11
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(150 KB)
MSDSshow(57.4 KB)
Interactions
Drug InteractionsSearched, but no interactions found.
Food InteractionsNot Available

Targets

1. Pyruvate-flavodoxin oxidoreductase

Kind: protein

Organism: Desulfovibrio africanus

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Pyruvate-flavodoxin oxidoreductase P94692 Details

References:

  1. Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG: Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrob Agents Chemother. 2007 Mar;51(3):868-76. Epub 2006 Dec 11. Pubmed
  2. Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Hoffman PS, Macdonald TL: Biological activity of modified and exchanged 2-amino-5-nitrothiazole amide analogues of nitazoxanide. Bioorg Med Chem Lett. 2010 Jun 15;20(12):3537-9. Epub 2010 May 18. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:24