Gimeracil

Identification

Summary

Gimeracil is a DPD inhibitor used as an adjunct to antineoplastic therapy to increase the systemic concentrations and therapeutic effectiveness of other antineoplastic agents.

Brand Names
Teysuno
Generic Name
Gimeracil
DrugBank Accession Number
DB09257
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 145.54
Monoisotopic: 144.9930561
Chemical Formula
C5H4ClNO2
Synonyms
  • 5-Chloro-2,4-dihydroxypyridine
  • 5-Chloro-4-hydroxy-2-pyridone
  • Gimeracil
  • gimestat
  • Teysuno
  • Ts-1 (TN)
External IDs
  • Ts-1 (TN)

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.

Pharmacology
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Associated Conditions
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Contraindications
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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
Humans
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

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Gimeracil which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Gimeracil which could result in a higher serum level.
AcrivastineGimeracil may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Gimeracil which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Gimeracil which could result in a higher serum level.
Interactions
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Food Interactions
  • Drink plenty of fluids. Drinking water is important to prevent dehydration when taking Teysuno.
  • Take on an empty stomach. Take Teysuno at least 1 hour before or after eating.

Products

Products2
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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
TeysunoGimeracil (4.35 mg) + Oteracil (11.8 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2016-09-08Not applicableEU flag
TeysunoGimeracil (5.8 mg) + Oteracil (15.8 mg) + Tegafur (20 mg)CapsuleOralNordic Group Bv2016-09-08Not applicableEU flag
TeysunoGimeracil (4.35 mg) + Oteracil (11.8 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2016-09-08Not applicableEU flag
TeysunoGimeracil (5.8 mg) + Oteracil (15.8 mg) + Tegafur (20 mg)CapsuleOralNordic Group Bv2016-09-08Not applicableEU flag
TeysunoGimeracil (4.35 mg) + Oteracil (11.8 mg) + Tegafur (15 mg)CapsuleOralNordic Group Bv2016-09-08Not applicableEU flag
TS-ONE CAPSULE 20Gimeracil (5.8 MG) + Oteracil potassium (19.6 MG) + Tegafur (20 MG)CapsuleOralบริษัท ดีทแฮล์ม เคลเลอร์ โลจิสติกส์ จำกัด2018-04-19Not applicableThailand flag
TS-ONE Capsule 20Gimeracil (5.8 mg) + Oteracil potassium (19.6 mg) + Tegafur (20 mg)CapsuleOralDKSH MALAYSIA SDN BHD2020-09-08Not applicableMalaysia flag
TS-ONE Capsule 20Gimeracil (5.8 mg) + Oteracil potassium (19.6 mg) + Tegafur (20 mg)CapsuleOralTAIHO PHARMA SINGAPORE PTE. LTD.2009-07-13Not applicable
TS-ONE CAPSULE 20Gimeracil (5.8 MG) + Oteracil potassium (19.6 MG) + Tegafur (20 MG)CapsuleOralบริษัท โอลิค (ประเทศไทย) จำกัด2019-01-07Not applicableThailand flag
TS-ONE CAPSULE 25Gimeracil (7.25 MG) + Oteracil potassium (24.5 MG) + Tegafur (25 MG)CapsuleOralบริษัท ดีทแฮล์ม เคลเลอร์ โลจิสติกส์ จำกัด2018-04-19Not applicableThailand flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Dihydropyridine / Heteroaromatic compound / Hydrocarbon derivative / Hydroxypyridine / Lactam / Organic nitrogen compound
show 9 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
UA8SE1325T
CAS number
103766-25-2
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

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. [Article]
  2. European Medicines Agency (EMA): TEYSUNO (tegafur/gimeracil/oteracil) Summary of Product Characteristics [Link]
KEGG Drug
D01846
PubChem Compound
54679224
PubChem Substance
310265159
ChemSpider
3353
ChEBI
31652
ChEMBL
CHEMBL1730601
ZINC
ZINC000013831809

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Unknown StatusTreatmentUnresectable Pancreatic Cancer1
3CompletedTreatmentColorectal Carcinoma (CRC)1
3CompletedTreatmentColorectal Carcinoma (CRC) / Metastases1
3CompletedTreatmentMalignant Neoplasm of Stomach2
3CompletedTreatmentMetastatic Diffuse Gastric Cancer Including Carcinoma of the Gastro-esophageal Junction1
3RecruitingTreatmentAdenocarcinomas / Chemoradiation / Gastroesophageal Cancer (GC) / Locally Advanced Cancer / Stomach Neoplasms1
3RecruitingTreatmentChemotherapy, Adjuvant / Stage III Colorectal Cancer1
3RecruitingTreatmentEsophageal Neoplasms Malignant1
3RecruitingTreatmentMalignant Neoplasm of Stomach3
3RecruitingTreatmentMalignant Neoplasm of Stomach / Stomach Neoplasms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, soluble
CapsuleOral
CapsuleOral5.8 mg
CapsuleOral7.25 mg
TabletOral
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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
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 16:31 / Updated on February 21, 2021 18:52