Tegafur-uracil

Identification

Generic Name
Tegafur-uracil
DrugBank Accession Number
DB09327
Background

Tegafur-uracil is an anti-tumor compound containing tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) and uracil in a molar ratio of 1:4. It was developed as an anti-cancer therapy by Taiho Pharmaceutical Co Ltd.1 It is approved in different countries but it is not yet approved by the FDA, Health Canada or EMA.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 312.257
Monoisotopic: 312.086997698
Chemical Formula
C12H13FN4O5
Synonyms
  • Tegafur/uracil
  • UFT
  • UFUR

Pharmacology

Indication

Tegafur-uracil is indicated for the first line treatment of metastatic colorectal cancer with concomitant administration of calcium folinate.8 Colorectal cancer is the third most diagnosed cancer and 30% of the cases can present the metastatic state.5

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Contraindications & Blackbox Warnings
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Pharmacodynamics

The use of the combination of tegafur and uracil allows increasing the oral bioavailability, improving the pharmacokinetic behavior of the delivered 5-fluoruracil and increasing the half-life of tegafur. The effect of this combo drug can ameliorate the usage by reducing the dosage frequency which tends to be uncomfortable for the patients.4 The effect of tegafur's metabolites results in a decreased thymidine synthesis, DNA synthesis, disrupted RNA function and tumor cell cytotoxicity.9

Mechanism of action

The generation of this combo was conceived under the reported activation by the transformation of tegafur to 5-fluorouracil. These findings have convened with results that suggested that the degradation of 5-fluorouracil can be depressed by the addition of uracil.1 Uracil competitively inhibits the catabolic action of dihydropyrimidine dehydrogenase. This combined activity allows a significant increase in blood and tissue 5-fluorouracil levels by inhibiting its first-pass hepatic metabolism.2,9 The active metabolites of tegafur inhibit the enzyme thymidylate synthase (5-fluoro-deoxyuridine-monophosphate) and intercalate into RNA (5-fluorouridine-triphosphate).9

TargetActionsOrganism
ADihydropyrimidine dehydrogenase [NADP(+)]
antagonist
Humans
AThymidylate synthase
antagonist
Humans
ARNANot AvailableHumans
ADNANot AvailableHumans
Absorption

The absorption into systemic circulation is very rapid and the peak concentration is reached within 1-2 hours. After a single dose of tegafur/uracil of 300 mg/m2/day in three divided doses, tegafur plasma concentration of >1000 ng/ml are maintained throughout the 8-hour dosing interval, whereas uracil concentrations decline rapidly following the peak concentration. The plasma concentration of 5-fluorouracil peaks at 30-60 min after administration with 200 ng/ml and remain detectable for 8-hour dosing interval. There is no significant long-term accumulation of either uracil, tegafur or 5-fluorouracil.8

Volume of distribution

The volume of distribution of tegafur is reported to be 59 L while the uracil volume of distribution of 474 L.6

Protein binding

The serum binding protein of tegafur is of 52% while the protein binding of uracil is negligible.8

Metabolism

Tegafur is bioactivated to 5-fluorouracil by the liver microsomal cytochrome P450 enzymes, mainly the CYP 2A6. This bioactivation is marked by the presence of C-5' oxidation and C-2' hydrolysis.8 The 5-fluorouracil is later transformed into its active metabolite 5-fluorodeoxyuridine-monophosphate and 5-fluorouridine-triphosphate.9 More than 80% of the administered dose is eliminated due to the metabolism of dihydropyridine dehydrogenase.4 Some other metabolic products include 3'-hydroxy tegafur, 4'-hydroxy tegafur and dihydro tegafur which all of them are significantly less cytotoxic than 5-fluorouracil.6

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Route of elimination

Less than 20% of the administered dose of tegafur is excreted intact in the urine following the oral administration.8

Half-life

The presence of uracil generates an increase in the half-life of tegafur and it is registered to be of 11 hours.4 The elimination half-life of uracil is of 20-40 minutes.8

Clearance

The reported clearance of tegafur when administered in the form of tegafur/uracil ranged from 47 to 175 ml/min

Adverse Effects
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Toxicity

High doses of tegafur are reported to present unique central nervous system toxicity. The oral administration of tegafur has been reported to present toxicity but the usage of the combo product tegafur/uracil have presented higher levels of 5-fluorouracil without the toxic effects or oral tegafur.10

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
AbataceptThe metabolism of Tegafur-uracil can be increased when combined with Abatacept.
AcetaminophenThe metabolism of Tegafur-uracil can be decreased when combined with Acetaminophen.
AdalimumabThe metabolism of Tegafur-uracil can be increased when combined with Adalimumab.
AmiodaroneThe metabolism of Tegafur-uracil can be decreased when combined with Amiodarone.
AmphetamineThe metabolism of Tegafur-uracil can be decreased when combined with Amphetamine.
Food Interactions
Not Available

Products

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International/Other Brands
Ftorafur (Taj pharma)

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Halopyrimidines
Alternative Parents
Pyrimidones / Aryl fluorides / Hydropyrimidines / Vinylogous amides / Heteroaromatic compounds / Tetrahydrofurans / Lactams / Ureas / Oxacyclic compounds / Azacyclic compounds
show 6 more
Substituents
Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Halopyrimidine / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Lactam / Organic nitrogen compound
show 12 more
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
HMI5GR78FR
CAS number
74578-38-4
InChI Key
DHMYGZIEILLVNR-UHFFFAOYSA-N
InChI
InChI=1S/C8H9FN2O3.C4H4N2O2/c9-5-4-11(6-2-1-3-14-6)8(13)10-7(5)12;7-3-1-2-5-4(8)6-3/h4,6H,1-3H2,(H,10,12,13);1-2H,(H2,5,6,7,8)
IUPAC Name
1,2,3,4-tetrahydropyrimidine-2,4-dione; 5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione
SMILES
O=C1NC=CC(=O)N1.FC1=CN(C2CCCO2)C(=O)NC1=O

References

General References
  1. Yamashita K, Sutou H, Maruden A, Takenouchi T, Morita K, Ariyoshi T: A nine-month chronic toxicity study of tegafur-uracil mixture (UFT) in dogs. J Toxicol Sci. 1988 May;13(2):97-132. [Article]
  2. Kim DJ, Kim TI, Suh JH, Cho YS, Shin SK, Kang JK, Kim NK, Kim WH: Oral tegafur-uracil plus folinic acid versus intravenous 5-fluorouracil plus folinic acid as adjuvant chemotherapy of colon cancer. Yonsei Med J. 2003 Aug 30;44(4):665-75. doi: 10.3349/ymj.2003.44.4.665. [Article]
  3. Inada T, Ogata Y, Kubota T, Ozawa I, Hishinuma S, Shimizu H, Kotake K, Ikeda T, Koyama Y: A pharmacodynamic and pharmacokinetic study of fluoropyrimidines in a nude mouse system and in postoperative patients with gastric cancer. Surg Today. 1993;23(8):687-92. [Article]
  4. Milano G, Ferrero JM, Francois E: Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer. 2004 Aug 16;91(4):613-7. [Article]
  5. Martini G, Troiani T, Cardone C, Vitiello P, Sforza V, Ciardiello D, Napolitano S, Della Corte CM, Morgillo F, Raucci A, Cuomo A, Selvaggi F, Ciardiello F, Martinelli E: Present and future of metastatic colorectal cancer treatment: A review of new candidate targets. World J Gastroenterol. 2017 Jul 14;23(26):4675-4688. doi: 10.3748/wjg.v23.i26.4675. [Article]
  6. Ashley C. and Dunleavy A. (2014). The renal drug handbook. Caroline Ashley and Aileen Dunleavy.
  7. Wellington K. and Goa K. (2001). Drugs and aging. Springer .
  8. UFT (uracil/tegafur) capsules_Product information [Link]
  9. National Cancer Institute [Link]
  10. FDA presentations [Link]
PubChem Compound
104747
PubChem Substance
310265209
ChemSpider
94558
Wikipedia
Tegafur-uracil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Unknown StatusNot AvailableMSI-L/MSS / Stage II Colon Cancer1
3CompletedTreatmentColorectal Cancer2
3Unknown StatusTreatmentColorectal Cancer2
3Unknown StatusTreatmentHead And Neck Cancer1
3Unknown StatusTreatmentNasopharyngeal Carcinoma (NPC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility14.0 mg/mLALOGPS
logP-0.09ALOGPS
logP0.024Chemaxon
logS-1.2ALOGPS
pKa (Strongest Acidic)8.08Chemaxon
pKa (Strongest Basic)-4.3Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area58.64 Å2Chemaxon
Rotatable Bond Count1Chemaxon
Refractivity44.5 m3·mol-1Chemaxon
Polarizability17.51 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-168.55536
predicted
DeepCCS 1.0 (2019)
[M+H]+170.91338
predicted
DeepCCS 1.0 (2019)
[M+Na]+177.00693
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. Kim DJ, Kim TI, Suh JH, Cho YS, Shin SK, Kang JK, Kim NK, Kim WH: Oral tegafur-uracil plus folinic acid versus intravenous 5-fluorouracil plus folinic acid as adjuvant chemotherapy of colon cancer. Yonsei Med J. 2003 Aug 30;44(4):665-75. doi: 10.3349/ymj.2003.44.4.665. [Article]
  2. National Cancer Institute [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Thymidylate synthase activity
Specific Function
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name
TYMS
Uniprot ID
P04818
Uniprot Name
Thymidylate synthase
Molecular Weight
35715.65 Da
References
  1. National Cancer Institute [Link]
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
References
  1. National Cancer Institute [Link]
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. National Cancer Institute [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. UFT (uracil/tegafur) capsules_Product information [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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. National Cancer Institute [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulf...
Gene Name
SLC22A7
Uniprot ID
Q9Y694
Uniprot Name
Solute carrier family 22 member 7
Molecular Weight
60025.025 Da
References
  1. 8. (2015). In Advances in Cancer Research (pp. 217-243). Elsevier.
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Nucleoside transmembrane transporter activity
Specific Function
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR...
Gene Name
SLC29A1
Uniprot ID
Q99808
Uniprot Name
Equilibrative nucleoside transporter 1
Molecular Weight
50218.805 Da
References
  1. 8. (2015). In Advances in Cancer Research (pp. 217-243). Elsevier.
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Nucleoside transmembrane transporter activity
Specific Function
Mediates equilibrative transport of purine, pyrimidine nucleosides and the purine base hypoxanthine. Very less sensitive than SLC29A1 to inhibition by nitrobenzylthioinosine (NBMPR), dipyridamole, ...
Gene Name
SLC29A2
Uniprot ID
Q14542
Uniprot Name
Equilibrative nucleoside transporter 2
Molecular Weight
50112.335 Da
References
  1. 8. (2015). In Advances in Cancer Research (pp. 217-243). Elsevier.
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Pyrimidine- and adenine-specific:sodium symporter activity
Specific Function
Sodium-dependent and pyrimidine-selective. Exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit) (selective for pyrimidine nucleosides and adenosine)....
Gene Name
SLC28A1
Uniprot ID
O00337
Uniprot Name
Sodium/nucleoside cotransporter 1
Molecular Weight
71583.18 Da
References
  1. 8. (2015). In Advances in Cancer Research (pp. 217-243). Elsevier.
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Purine nucleoside transmembrane transporter activity
Specific Function
Sodium-dependent and purine-selective transporter. Exhibits the transport characteristics of the nucleoside transport system cif or N1 subtype (N1/cif) (selective for purine nucleosides and uridine...
Gene Name
SLC28A2
Uniprot ID
O43868
Uniprot Name
Sodium/nucleoside cotransporter 2
Molecular Weight
71925.565 Da
References
  1. 8. (2015). In Advances in Cancer Research (pp. 217-243). Elsevier.
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Pyrimidine- and adenine-specific:sodium symporter activity
Specific Function
Sodium-dependent, pyrimidine- and purine-selective. Involved in the homeostasis of endogenous nucleosides. Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtyp...
Gene Name
SLC28A3
Uniprot ID
Q9HAS3
Uniprot Name
Solute carrier family 28 member 3
Molecular Weight
76929.61 Da
References
  1. 8. (2015). In Advances in Cancer Research (pp. 217-243). Elsevier.

Drug created at November 17, 2015 19:06 / Updated at June 12, 2020 16:52