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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Tegafur-uracil (DB09327)

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Weight

Average: 312.257
Monoisotopic: 312.086997698

Chemical Formula

C₁₂H₁₃FN₄O₅

Synonyms

• Tegafur/uracil
• UFT
• UFUR

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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

Target	Actions	Organism
ADihydropyrimidine dehydrogenase [NADP(+)]	antagonist	Humans
AThymidylate synthase	antagonist	Humans
ARNA	Not Available	Humans
ADNA	Not Available	Humans

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

Hover over products below to view reaction partners

• Tegafur-uracil
  • 3-hydroxytegafur + 4-hydroxytegafur + 5-hydroxytegafur + dihydrotegafur
    • 5-fluorouracil
      • 5-fluorodeoxyuridine-monophosphate + 5-fluorouridine-triphosphate
      • 5-FUH2
        • FUPA
          • FBAL + Urea

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

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Not Available

Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abatacept	The metabolism of Tegafur-uracil can be increased when combined with Abatacept.
Acetaminophen	The metabolism of Tegafur-uracil can be decreased when combined with Acetaminophen.
Adalimumab	The metabolism of Tegafur-uracil can be increased when combined with Adalimumab.
Amiodarone	The metabolism of Tegafur-uracil can be decreased when combined with Amiodarone.
Amphetamine	The metabolism of Tegafur-uracil can be decreased when combined with Amphetamine.

Food Interactions

Not Available

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International/Other Brands

Ftorafur (Taj pharma)

Categories

Drug Categories

• Cytochrome P-450 CYP2A6 Substrates
• Cytochrome P-450 Substrates

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 / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives

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Substituents

Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Halopyrimidine / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Lactam / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Pyrimidone / Tetrahydrofuran / Urea / Vinylogous amide

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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]

External Links

PubChem Compound

104747

PubChem Substance

310265209

ChemSpider

94558

Wikipedia

Tegafur-uracil

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Unknown Status	Not Available	MSI-L/MSS / Stage II Colon Cancer	1
3	Completed	Treatment	Colorectal Cancer	2
3	Unknown Status	Treatment	Colorectal Cancer	2
3	Unknown Status	Treatment	Head And Neck Cancer	1
3	Unknown Status	Treatment	Nasopharyngeal 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

Property	Value	Source
Water Solubility	14.0 mg/mL	ALOGPS
logP	-0.09	ALOGPS
logP	0.024	Chemaxon
logS	-1.2	ALOGPS
pKa (Strongest Acidic)	8.08	Chemaxon
pKa (Strongest Basic)	-4.3	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	58.64 Å2	Chemaxon
Rotatable Bond Count	1	Chemaxon
Refractivity	44.5 m3·mol-1	Chemaxon
Polarizability	17.51 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[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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Details1. Dihydropyrimidine dehydrogenase [NADP(+)]

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]

Details2. Thymidylate synthase

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]

Details3. RNA

Kind

Nucleotide

Organism

Humans

Pharmacological action

Yes

References

1. National Cancer Institute [Link]

Details4. DNA

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]

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