Identification

Name
Gimeracil
Accession Number
DB09257
Type
Small Molecule
Groups
Approved
Description

Gimeracil is an adjunct to antineoplastic therapy, used to increase the concentration and effect of the main active componets within chemotherapy regimens. Approved by the European Medicines Agency (EMA) in March 2011, Gimeracil is available in combination with Oteracil 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.

Gimeracil's main role within Teysuno is to prevent the breakdown of Fluorouracil (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells [2]. It functions by reversibly and selectively blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU [1]. This allows higher concentrations of 5-FU to be achieved with a lower dose of tegafur, thereby also reducing toxic side effects.

Structure
Thumb
Synonyms
  • 5-Chloro-2,4-dihydroxypyridine
  • 5-Chloro-4-hydroxy-2-pyridone
  • gimestat
  • Teysuno
  • Ts-1 (TN)
External IDs
Ts-1 (TN)
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
TeysunoGimeracil (5.8 mg) + Oteracil (15.8 mg) + Tegafur (20 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoGimeracil (4.35 mg) + Oteracil (11.8 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoGimeracil (5.8 mg) + Oteracil (15.8 mg) + Tegafur (20 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoGimeracil (4.35 mg) + Oteracil (11.8 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
TeysunoGimeracil (4.35 mg) + Oteracil (11.8 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2011-03-14Not applicableEu
International/Other Brands
Teysuno
Categories
Not Available
UNII
UA8SE1325T
CAS number
103766-25-2
Weight
Average: 145.54
Monoisotopic: 144.9930561
Chemical Formula
C5H4ClNO2
InChI Key
ZPLQIPFOCGIIHV-UHFFFAOYSA-N
InChI
InChI=1S/C5H4ClNO2/c6-3-2-7-5(9)1-4(3)8/h1-2H,(H2,7,8,9)
IUPAC Name
5-chloro-4-hydroxy-1,2-dihydropyridin-2-one
SMILES
OC1=CC(=O)NC=C1Cl

Pharmacology

Indication

Gimeracil is used as an adjunct to antineoplastic therapy. When used within the product Teysuno, gimeracil 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

Gimeracil's main role within Teysuno is to prevent the breakdown of Fluorouracil (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells [2]. It functions by reversibly blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU [1].

TargetActionsOrganism
NDihydropyrimidine dehydrogenase [NADP(+)]
inhibitor
Human
Absorption

Mean 5-FU maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were approximately 3-fold higher after Teysuno administration than after administration of tegafur alone, despite a 16-fold lower Teysuno dose (50 mg of tegafur) compared to tegafur alone (800 mg), and are attributed to inhibition of DPD by gimeracil. Maximum plasma uracil concentration was observed at 4 hours, with a return to baseline levels within approximately 48 hours after dosing, indicating the reversibility of the DPD inhibition by gimeracil.

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 [2].

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 [2].

Protein binding

Oteracil, gimeracil, 5-FU, and tegafur are 8.4%, 32.2%, 18.4%, and 52.3% protein bound, respectively [2].

Metabolism
Not Available
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 [2].

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 [2].

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

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Gimeracil which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Gimeracil which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineGimeracil may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Gimeracil which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Harada K, Ferdous T, Harada T, Takenawa T, Ueyama Y: Gimeracil enhances the antitumor effect of cisplatin in oral squamous cell carcinoma cells in vitro and in vivo. Oncol Lett. 2017 Sep;14(3):3349-3356. doi: 10.3892/ol.2017.6602. Epub 2017 Jul 18. [PubMed:28927087]
  2. European Medicines Agency (EMA): TEYSUNO (tegafur/gimeracil/oteracil) Summary of Product Characteristics [Link]
External Links
KEGG Drug
D01846
PubChem Compound
54679224
PubChem Substance
310265159
ChemSpider
3353
ChEBI
31652
ChEMBL
CHEMBL1730601

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingTreatmentEsophageal Cancers1
1RecruitingTreatmentHepatocellular,Carcinoma2
1, 2RecruitingTreatmentAdenocarcinoma,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
2RecruitingTreatmentEsophageal1
2RecruitingTreatmentMalignant Neoplasm of Pancreas / Neoadjuvant Chemotherapy1
2RecruitingTreatmentMalignant Neoplasm of Stomach2
2RecruitingTreatmentMetastatic Colon Cancer1
2RecruitingTreatmentNeoplasms, Head and Neck1
2RecruitingTreatmentSafety and Effectiveness of Apatinib Combined With SOX Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer1
2TerminatedTreatmentEsophagus Cancer / Malignant Neoplasm of Colon / Malignant Neoplasm of Stomach / Rectum Cancer / Small Bowel Cancer1
2, 3Active Not RecruitingTreatmentMalignant Neoplasm of Stomach1
2, 3TerminatedTreatmentEsophageal Cancers1
3CompletedTreatmentColorectal Cancers / Metastases1
3RecruitingTreatmentMalignant Neoplasm of Stomach / Stomach Neoplasms1
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 Solubility14.2 mg/mLALOGPS
logP-0.08ALOGPS
logP0.13ChemAxon
logS-1ALOGPS
pKa (Strongest Acidic)8.66ChemAxon
pKa (Strongest Basic)-4.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area49.33 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity34.65 m3·mol-1ChemAxon
Polarizability12.19 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
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 pyridinones. These are compounds containing a pyridine ring, which bears a ketone.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Hydropyridines
Direct Parent
Pyridinones
Alternative Parents
Hydroxypyridines / Dihydropyridines / Aryl chlorides / Vinylogous acids / Heteroaromatic compounds / Lactams / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds
show 3 more
Substituents
Dihydropyridine / Pyridinone / Hydroxypyridine / Aryl chloride / Aryl halide / Vinylogous acid / Heteroaromatic compound / Lactam / Azacycle / Hydrocarbon derivative
show 9 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Protein homodimerization activity
Specific Function
Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil.
Gene Name
DPYD
Uniprot ID
Q12882
Uniprot Name
Dihydropyrimidine dehydrogenase [NADP(+)]
Molecular Weight
111400.32 Da
References
  1. European Medicines Agency (EMA): TEYSUNO (tegafur/gimeracil/oteracil) Summary of Product Characteristics [Link]

Drug created on October 26, 2015 10:31 / Updated on August 02, 2018 06:16