Tegafur

Last updated
Tegafur
Tegafur.svg
Tegafur-3D-balls.png
Clinical data
Other names5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione
AHFS/Drugs.com International Drug Names
License data
Pregnancy
category
  • AU:D
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Elimination half-life 3.9-11 hours
Identifiers
  • (RS)-5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.038.027 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H9FN2O3
Molar mass 200.169 g·mol−1
3D model (JSmol)
  • FC=1C(=O)NC(=O)N(C=1)[C@@H]2OCCC2
  • InChI=1S/C8H9FN2O3/c9-5-4-11(6-2-1-3-14-6)8(13)10-7(5)12/h4,6H,1-3H2,(H,10,12,13)/t6-/m1/s1 Yes check.svgY
  • Key:WFWLQNSHRPWKFK-ZCFIWIBFSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU. [1]

Contents

It was patented in 1967 and approved for medical use in 1972. [2]

Medical uses

As a prodrug to 5-FU it is used in the treatment of the following cancers: [3]

It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil. [3] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil). [3]

Adverse effects

The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea). [3] Gastrointestinal toxicity is the dose-limiting side effect of tegafur. [3] Central neurotoxicity is more common with tegafur than with fluorouracil. [3]

Pharmacogenetics

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur. [5] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency. [5] [6] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome. [5] [6]

Mechanism of action

It is a prodrug to 5-FU, which is a thymidylate synthase inhibitor. [3]

Pharmacokinetics

It is metabolised to 5-FU by CYP2A6. [7] [8]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:
FluoropyrimidineActivity WP1601.png go to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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FluoropyrimidineActivity WP1601.png go to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
|alt=Fluorouracil (5-FU) Activity edit]]
Fluorouracil (5-FU) Activity edit
  1. The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

See also

Related Research Articles

<span class="mw-page-title-main">Uridine monophosphate synthase</span> Protein-coding gene in the species Homo sapiens

The enzyme Uridine monophosphate synthase catalyses the formation of uridine monophosphate (UMP), an energy-carrying molecule in many important biosynthetic pathways. In humans, the gene that codes for this enzyme is located on the long arm of chromosome 3 (3q13).

Fluorouracil, sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

<span class="mw-page-title-main">Capecitabine</span> Chemical compound

Capecitabine, sold under the brand name Xeloda among others, is a anticancer medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth.

<span class="mw-page-title-main">Thiopurine methyltransferase</span>

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

<span class="mw-page-title-main">Brivudine</span> Chemical compound

Brivudine is an antiviral drug used in the treatment of herpes zoster ("shingles"). Like other antivirals, it acts by inhibiting replication of the target virus.

<span class="mw-page-title-main">Dihydropyrimidine dehydrogenase deficiency</span> Medical condition

Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.

<span class="mw-page-title-main">Thymidylate synthase</span> Enzyme

Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

<span class="mw-page-title-main">Dihydropyrimidine dehydrogenase (NADP+)</span> Class of enzymes

In enzymology, a dihydropyrimidine dehydrogenase (NADP+) (EC 1.3.1.2) is an enzyme that catalyzes the chemical reaction

Tegafur/uracil is a chemotherapy drug combination used in the treatment of cancer, primarily bowel cancer. It is also called UFT or UFUR.

<span class="mw-page-title-main">SMUG1</span> Protein-coding gene in the species Homo sapiens

Single-strand selective monofunctional uracil DNA glycosylase is an enzyme that in humans is encoded by the SMUG1 gene. SMUG1 is a glycosylase that removes uracil from single- and double-stranded DNA in nuclear chromatin, thus contributing to base excision repair.

<span class="mw-page-title-main">Sorivudine</span> Chemical compound

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<span class="mw-page-title-main">DPYS</span> Protein-coding gene in the species Homo sapiens

Dihydropyrimidinase is an enzyme that in humans is encoded by the DPYS gene.

<span class="mw-page-title-main">UPB1</span> Protein-coding gene in the species Homo sapiens

Beta-ureidopropionase is an enzyme that in humans is encoded by the UPB1 gene.

<span class="mw-page-title-main">Carmofur</span> Chemical compound

Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lipophilic-masked analog of 5-FU that can be administered orally.

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<span class="mw-page-title-main">Trifluridine/tipiracil</span> Combination medication

Trifluridine/tipiracil (FTD–TPI), sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

Tegafur/gimeracil/oteracil, sold under the brand name Teysuno among others is a fixed-dose combination medication used for the treatment of advanced gastric cancer when used in combination with cisplatin, and also for the treatment of head and neck cancer, colorectal cancer, non–small-cell lung, breast, pancreatic, and biliary tract cancers.

<span class="mw-page-title-main">Doxifluridine</span> Nucleoside analog prodrug

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<span class="mw-page-title-main">Fluorodeoxyuridylate</span> Chemical compound

Fluorodeoxyuridylate, also known as FdUMP, 5-fluoro-2'-deoxyuridylate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate, is a molecule formed in vivo from 5-fluorouracil and 5-fluorodeoxyuridine.

<span class="mw-page-title-main">Cancer pharmacogenomics</span>

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References

  1. El Sayed YM, Sadée W (September 1983). "Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes". Cancer Research. 43 (9): 4039–4044. PMID   6409396.
  2. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 511. ISBN   9783527607495.
  3. 1 2 3 4 5 6 7 Sweetman S, ed. (14 November 2011). "Martindale: The Complete Drug Reference". Pharmaceutical Press. Retrieved 12 February 2014.
  4. Ishikawa T (May 2008). "Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma". World Journal of Gastroenterology. 14 (18): 2797–2801. doi: 10.3748/wjg.14.2797 . PMC   2710718 . PMID   18473401.
  5. 1 2 3 Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M (December 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics. 94 (6): 640–645. doi:10.1038/clpt.2013.172. PMC   3831181 . PMID   23988873.
  6. 1 2 Amstutz U, Froehlich TK, Largiadèr CR (September 2011). "Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity". Pharmacogenomics. 12 (9): 1321–1336. doi:10.2217/pgs.11.72. PMID   21919607.
  7. Nakayama T, Noguchi S (January 2010). "Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan". The Oncologist. 15 (1): 26–36. doi:10.1634/theoncologist.2009-0255. PMC   3227888 . PMID   20080863.
  8. Matt P, van Zwieten-Boot B, Calvo Rojas G, Ter Hofstede H, Garcia-Carbonero R, Camarero J, et al. (October 2011). "The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP)". The Oncologist. 16 (10): 1451–1457. doi:10.1634/theoncologist.2011-0224. PMC   3228070 . PMID   21963999.