Identification

Name
Nitazoxanide
Accession Number
DB00507  (APRD00558)
Type
Small Molecule
Groups
Approved, Investigational, Vet Approved
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
  • Adrovet
  • Nitaxozanid
  • Nitaxozanide
  • Nitazoxanida
  • Nitazoxanidum
  • Nodik
  • Omniparax
External IDs
PH 5776
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AliniaPowder, for suspension100 mg/5mLOralLupin Pharma2013-10-09Not applicableUs
AliniaTablet500 mg/1OralRomark Laboratories, L.C.2004-07-21Not applicableUs
AliniaTablet500 mg/1OralAvera Mc Kennan Hospital2015-05-26Not applicableUs
AliniaPowder, for suspension100 mg/5mLOralRomark Laboratories, L.C.2002-11-22Not applicableUs
International/Other Brands
Alinia / Alpex Nizox (Alpex Pharmaceutical) / ANNITA (Alpex Pharmaceutical) / Azoxanid (G&R) / Celectan (Farma) / Colufase (Roemmers) / Coluquim (Quilab) / Daxon (Siegfried) / Dianide (General Pharma) / Diar (ACI) / Famidox (Lafrancol) / Kaside (Lafrancol) / Kazide (Lafrancol) / Larvisol (Armofar) / Lumbris (Farmedic) / Mixel (California) / Niazid (Apex) / Nitax (Delta) / Nitaxide (Beximco) / Nitazet (Glenmark) / Nitazofin (Bussié)
Categories
UNII
SOA12P041N
CAS number
55981-09-4
Weight
Average: 307.282
Monoisotopic: 307.026291103
Chemical Formula
C12H9N3O5S
InChI Key
YQNQNVDNTFHQSW-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

Pharmacology

Indication

For 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.

Structured Indications
Pharmacodynamics

Nitazoxanide 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 action

The 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.

TargetActionsOrganism
APyruvate-flavodoxin oxidoreductase
inhibitor
Desulfovibrio africanus
Absorption

The 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 distribution
Not Available
Protein binding

Very 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.

Route of elimination

Tizoxanide 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 life

3.5 hours in patients with normal renal function

Clearance
Not Available
Toxicity

In 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

Synthesis Reference
US3950351
General References
  1. Authors unspecified: Parasitic infections. Am J Transplant. 2004 Nov;4 Suppl 10:142-55. [PubMed:15504227]
External Links
Human Metabolome Database
HMDB14649
KEGG Drug
D02486
PubChem Compound
41684
PubChem Substance
46507813
ChemSpider
38037
BindingDB
50075050
ChEBI
94807
ChEMBL
CHEMBL1401
Therapeutic Targets Database
DAP001293
PharmGKB
PA164754874
HET
NTI
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Nitazoxanide
ATC Codes
P01AX11 — Nitazoxanide
PDB Entries
3v35
FDA label
Download (150 KB)
MSDS
Download (57.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedPreventionHepatitis C Recurrence1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1, 2CompletedTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1
2Active Not RecruitingTreatmentSevere Acute Respiratory Illness1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection4
2CompletedTreatmentClostridium Difficile1
2CompletedTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentHepatitis C Infection / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentInfections, Rotavirus / Viral Gastroenteritis Due to Rotavirus1
2Not Yet RecruitingTreatmentGastroenteritis Norovirus1
2RecruitingTreatmentGastroenteritis1
2RecruitingTreatmentTuberculosis1
2TerminatedTreatmentCrohn's Disease (CD)1
2TerminatedTreatmentFlu caused by Influenza1
2Unknown StatusTreatmentHCV Coinfection / Human Immunodeficiency Virus (HIV) Infections1
2Unknown StatusTreatmentHepatic Encephalopathy1
2WithdrawnTreatmentBronchiolitis1
2, 3CompletedTreatmentAdenoviridae Infections / Infections, Rotavirus / Norovirus Infections1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
2, 3CompletedTreatmentFlu caused by Influenza1
2, 3CompletedTreatmentHepatitis C Viral Infection1
2, 3RecruitingTreatmentCognitive Development / Enteric Pathogens / Malnutrition / Stunting1
2, 3RecruitingTreatmentHepatic Encephalopathy1
3CompletedTreatmentAmebiasis2
3CompletedTreatmentClostridium Enterocolitis / Pseudomembranous Colitis1
3CompletedTreatmentDiarrhea1
3CompletedTreatmentFlu caused by Influenza2
3Not Yet RecruitingTreatmentFlu caused by Influenza1
3RecruitingTreatmentHelicobacter-associated Gastritis1
3RecruitingTreatmentIndigestion1
3TerminatedTreatmentClostridium Infections1
3TerminatedTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Type 2 Diabetes Mellitus1
4CompletedTreatmentIrritable Bowel Syndrome (IBS)1
4Unknown StatusTreatmentChronic Hepatitis C Virus (HCV) Infection1
Not AvailableCompletedTreatmentDiarrhea / Infections, Rotavirus1
Not AvailableCompletedTreatmentHepatic Cirrhosis / Minimal Hepatic Encephalopathy1
Not AvailableUnknown StatusTreatmentCryptosporidiosis infection / Human Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
  • Romark laboratories
Packagers
Dosage forms
FormRouteStrength
Powder, for suspensionOral100 mg/5mL
TabletOral500 mg/1
Prices
Unit descriptionCostUnit
Alinia 500 mg tablet23.22USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5387598No1995-02-072012-02-07Us
US5968961No1997-05-072017-05-07Us
US5965590No1997-07-032017-07-03Us
US6117894No1997-05-072017-05-07Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)202 °CNot Available
logP1.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00755 mg/mLALOGPS
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 Area114.11 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity73.89 m3·mol-1ChemAxon
Polarizability27.54 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9045
Blood Brain Barrier+0.7175
Caco-2 permeable-0.5571
P-glycoprotein substrateNon-substrate0.7978
P-glycoprotein inhibitor INon-inhibitor0.8874
P-glycoprotein inhibitor IINon-inhibitor0.9836
Renal organic cation transporterNon-inhibitor0.9228
CYP450 2C9 substrateNon-substrate0.7438
CYP450 2D6 substrateNon-substrate0.8431
CYP450 3A4 substrateNon-substrate0.5596
CYP450 1A2 substrateNon-inhibitor0.6339
CYP450 2C9 inhibitorInhibitor0.6655
CYP450 2D6 inhibitorNon-inhibitor0.9027
CYP450 2C19 inhibitorNon-inhibitor0.6341
CYP450 3A4 inhibitorInhibitor0.6669
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5635
Ames testAMES toxic0.8322
CarcinogenicityNon-carcinogens0.7746
BiodegradationReady biodegradable0.5458
Rat acute toxicity1.7902 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9283
hERG inhibition (predictor II)Non-inhibitor0.9295
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-01b9-1950000000-3d1aca26d9cbdaaab410

Taxonomy

Description
This compound belongs to the class of organic compounds known as acylsalicylamides. These are o-acylated derivatives of salicylamide.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Acylsalicylamides
Alternative Parents
Phenol esters / Benzamides / Phenoxy compounds / Benzoyl derivatives / Nitroaromatic compounds / Nitrothiazoles / 2,5-disubstituted thiazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Carboxylic acid esters
show 10 more
Substituents
Acylsalicylamide / Phenol ester / Benzamide / Phenoxy compound / Nitroaromatic compound / Benzoyl / Nitrothiazole / 2,5-disubstituted 1,3-thiazole / Azole / Thiazole
show 24 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Desulfovibrio africanus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thiamine pyrophosphate binding
Specific Function
Catalyzes the ferredoxin-dependent oxidative decarboxylation of pyruvate. Required for the transfer of electrons from pyruvate to ferredoxin (PubMed:9294422, PubMed:7612653). Ferredoxin I and ferre...
Gene Name
por
Uniprot ID
P94692
Uniprot Name
Pyruvate synthase
Molecular Weight
133679.405 Da
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:17158936]
  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. doi: 10.1016/j.bmcl.2010.04.126. Epub 2010 May 18. [PubMed:20488706]

Drug created on June 13, 2005 07:24 / Updated on November 07, 2017 01:39