Chemistry:Tegafur

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Short description: Chemical compound
Tegafur
Skeletal formula of tegafur
Ball-and-stick model of the tegafur molecule
Clinical data
Other names5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione
AHFS/Drugs.comInternational 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-life3.9-11 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC8H9FN2O3
Molar mass200.169 g·mol−1
3D model (JSmol)
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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]

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

See also

  • Tegafur/uracil
  • Tegafur/gimeracil/oteracil

References

  1. "Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes". Cancer Research 43 (9): 4039–4044. September 1983. PMID 6409396. 
  2. (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 511. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511. 
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Martindale: The Complete Drug Reference". Pharmaceutical Press. 14 November 2011. http://www.medicinescomplete.com/mc/martindale/current/1866-m.htm. 
  4. "Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma". World Journal of Gastroenterology 14 (18): 2797–2801. May 2008. doi:10.3748/wjg.14.2797. PMID 18473401. 
  5. 5.0 5.1 5.2 "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics 94 (6): 640–645. December 2013. doi:10.1038/clpt.2013.172. PMID 23988873. 
  6. 6.0 6.1 "Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity". Pharmacogenomics 12 (9): 1321–1336. September 2011. doi:10.2217/pgs.11.72. PMID 21919607. 
  7. "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. January 2010. doi:10.1634/theoncologist.2009-0255. PMID 20080863. 
  8. "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. October 2011. doi:10.1634/theoncologist.2011-0224. PMID 21963999.