Oteracil

Identification

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Name
Oteracil
Accession Number
DB03209  (EXPT02456)
Type
Small Molecule
Groups
Approved
Description

Oteracil is an adjunct to antineoplastic therapy, used to reduce the toxic side effects associated with chemotherapy. Approved by the European Medicines Agency (EMA) in March 2011, Oteracil is available in combination with Gimeracil and Tegafur within the commercially available product "Teysuno". The main active ingredient in Teysuno is Tegafur, a pro-drug of Fluorouracil (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called "pyrimidines" that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth.

Oteracil's main role within Teysuno is to reduce the activity of 5-FU within normal gastrointestinal mucosa, and therefore reduce's gastrointestinal toxicity 1. It functions by blocking the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the production of 5-FU.

Structure
Thumb
Synonyms
  • 5-azaorotic acid
  • Allantoxanic acid
  • Oteracil
  • Oxonate
  • Oxonic Acid
Product Ingredients
IngredientUNIICASInChI Key
Oteracil potassium4R7FFA00RX2207-75-2IAPCTXZQXAVYNG-UHFFFAOYSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
TeysunoOteracil (15.8 mg) + Gimeracil (5.8 mg) + Tegafur (20 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoOteracil (15.8 mg) + Gimeracil (5.8 mg) + Tegafur (20 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoOteracil (11.8 mg) + Gimeracil (4.35 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoOteracil (11.8 mg) + Gimeracil (4.35 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoOteracil (11.8 mg) + Gimeracil (4.35 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
Categories
UNII
5VT6420TIG
CAS number
937-13-3
Weight
Average: 157.0843
Monoisotopic: 157.012355599
Chemical Formula
C4H3N3O4
InChI Key
RYYCJUAHISIHTL-UHFFFAOYSA-N
InChI
InChI=1S/C4H3N3O4/c8-2(9)1-5-3(10)7-4(11)6-1/h(H,8,9)(H2,5,6,7,10,11)
IUPAC Name
4,6-dioxo-1,4,5,6-tetrahydro-1,3,5-triazine-2-carboxylic acid
SMILES
OC(=O)C1=NC(=O)NC(=O)N1

Pharmacology

Indication

Oteracil is used as an adjunct to antineoplastic therapy. When used within the product Teysuno, oteracil is indicated for the treatment of adults with advanced gastric (stomach) cancer when given in combination with cisplatin.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Oteracil's main role within Teysuno is to reduce the activity of 5-FU within normal gastrointestinal mucosa, and therefore reduce's gastrointestinal toxicity 1. It functions by blocking the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the production of 5-FU.

Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

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Additional Data Available
Blackbox Warnings

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Absorption

After administration of a single dose of 50 mg Teysuno (expressed as tegafur content), median Tmax for Teysuno components tegafur, gimeracil, and oteracil was 0.5, 1.0, and 2.0 hours, respectively 1.

Volume of distribution

Although no intravenous data are available for Teysuno in humans, the volume of distribution could be roughly estimated from the apparent volume of distribution and urinary excretion data as 16 l/m2, 17 l/m2, and 23 l/m2 for tegafur, gimeracil and oteracil, respectively 1.

Protein binding

Oteracil, gimeracil, 5-FU, and tegafur are 8.4%, 32.2%, 18.4%, and 52.3% protein bound, respectively 1.

Metabolism

Based on the results of in vitro studies, a part of oteracil is non-enzymatically degraded to 5-azauracil (5-AZU) by gastric fluid, and is then converted to cyanuric acid (CA) in the digestive tract. Only a small amount of oteracil is metabolised in the liver because of its low permeability 1.

Route of elimination

Following a single dose of Teysuno, approximately 3.8% to 4.2% of administered tegafur, 65% to 72% of administered gimeracil, and 3.5% to 3.9% of administered oteracil were excreted unchanged in the urine 1.

Half life

Following a single dose of Teysuno, T1/2 values ranged from 6.7 to 11.3 hours for tegafur, from 3.1 to 4.1 hours for gimeracil, and from 1.8 to 9.5 hours for oteracil 1.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AllopurinolThe therapeutic efficacy of Oteracil can be decreased when used in combination with Allopurinol.
Additional Data Available
  • Extended Description
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    Severity

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Food Interactions
Not Available

References

Synthesis Reference
US6090940
General References
  1. European Medicines Agency (EMA): TEYSUNO (tegafur/gimeracil/oteracil) Summary of Product Characteristics [Link]
External Links
KEGG Drug
D06399
PubChem Compound
4604
PubChem Substance
46508346
ChemSpider
4443
ChEBI
30863
ChEMBL
CHEMBL181932
HET
OXC

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingTreatmentEsophageal Cancers1
1RecruitingTreatmentHepatocellular,Carcinoma2
1, 2Active Not RecruitingTreatmentAdenocarcinoma,Stomach / Esophagogastric Junction Adenocarcinoma1
2Active Not RecruitingTreatmentBiliary Tract Neoplasms1
2CompletedTreatmentStomach Neoplasms1
2RecruitingTreatmentAdenocarcinoma Of Esophagus / Adenocarcinomas of the Gastroesophageal Junction / Gastric Adenocarcinoma / Metastatic Esophagogastric Adenocarcinoma / Neoplasm, Gastric / Neoplasms, Esophageal / Unresectable, Locally Advanced or Metastatic, Adenocarcinoma of the Stomach, or of the Gastro Esophageal Junction1
2RecruitingTreatmentBile Duct Neoplasms / Cancer of Unknown Primary Site / Gastrointestinal Cancers / Malignant Neoplasm of Pancreas1
2RecruitingTreatmentMalignant Neoplasm of Stomach1
2RecruitingTreatmentNeoplasms, Head and Neck1
2TerminatedTreatmentEsophagus Cancer / Malignant Neoplasm of Colon / Malignant Neoplasm of Stomach / Rectum Cancer / Small Bowel Cancer1
2, 3TerminatedTreatmentEsophageal Cancers1
3CompletedTreatmentColorectal Cancers / Metastases1
3RecruitingTreatmentChemotherapy, Adjuvant / Colorectal Cancer Stage III1
3TerminatedTreatmentMetastatic Breast Cancer (MBC)1
3Unknown StatusTreatmentMalignant Neoplasm of Stomach1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility7.15 mg/mLALOGPS
logP-1.1ALOGPS
logP-1.2ChemAxon
logS-1.3ALOGPS
pKa (Strongest Acidic)2.14ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area107.86 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity29.7 m3·mol-1ChemAxon
Polarizability11.88 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6506
Blood Brain Barrier+0.817
Caco-2 permeable-0.8077
P-glycoprotein substrateNon-substrate0.703
P-glycoprotein inhibitor INon-inhibitor0.9932
P-glycoprotein inhibitor IINon-inhibitor1.0
Renal organic cation transporterNon-inhibitor0.9684
CYP450 2C9 substrateNon-substrate0.705
CYP450 2D6 substrateNon-substrate0.8199
CYP450 3A4 substrateNon-substrate0.8073
CYP450 1A2 substrateNon-inhibitor0.6205
CYP450 2C9 inhibitorNon-inhibitor0.959
CYP450 2D6 inhibitorNon-inhibitor0.9326
CYP450 2C19 inhibitorNon-inhibitor0.9364
CYP450 3A4 inhibitorNon-inhibitor0.935
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity1.0
Ames testNon AMES toxic0.9277
CarcinogenicityNon-carcinogens0.9449
BiodegradationReady biodegradable0.5369
Rat acute toxicity1.6818 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9804
hERG inhibition (predictor II)Non-inhibitor0.9803
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as triazinones. These are compounds containing a triazine ring which bears a ketone group a carbon atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Triazines
Sub Class
Triazinones
Direct Parent
Triazinones
Alternative Parents
1,3,5-triazines / Heteroaromatic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Triazinone / 1,3,5-triazine / Heteroaromatic compound / Azacycle / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
monocarboxylic acid, 1,3,5-triazines (CHEBI:30863)

Drug created on June 13, 2005 07:24 / Updated on June 04, 2019 05:46