Capecitabine

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Capecitabine
Capecitabine.svg
Capecitabine-from-xtal-2009-3D-balls.png
Systematic (IUPAC) name
Pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate
Clinical data
Trade names Xeloda
AHFS/Drugs.com monograph
MedlinePlus a699003
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability Extensive
Protein binding < 60%
Metabolism Hepatic, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active fluorouracil
Half-life 38–45 minutes
Excretion Renal (95.5%), faecal (2.6%)
Identifiers
CAS number 154361-50-9 YesY
ATC code L01BC06
PubChem CID 60953
DrugBank DB01101
ChemSpider 54916 YesY
UNII 6804DJ8Z9U YesY
KEGG D01223 YesY
ChEBI CHEBI:31348 YesY
ChEMBL CHEMBL1773 YesY
Chemical data
Formula C15H22FN3O6 
Mol. mass 359.35 g/mol
 YesY (what is this?)  (verify)

Capecitabine (INN) /kpˈstəbn/ (Xeloda, Roche) is an orally-administered chemotherapeutic agent used in the treatment of numerous cancers.[1] Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil (5-FU) in the body.[2]

Medical uses[edit]

It is used in the treatment of the following cancers:[1][2][3]

  • Colorectal cancer (either as neoadjuvant therapy with radiation, adjuvant therapy or for metastatic cases)
  • Breast cancer (metastatic or as monotherapy/combotherapy; this is licensed as a second-line treatment in the UK)
  • Gastric cancer (off-label in the US; this is a licensed indication in the UK)
  • Oesophageal cancer (off-label in the US)

Adverse effects[edit]

Adverse effects by frequency:[4][5][6][7]

Very common (>10% frequency)

Notes on adverse effects:

Contraindications[edit]

Contraindications include:[6]

  • History of hypersensitivity to fluorouacil, capecitabine or any of its excipients.
  • Patients with DPD deficiency (see Pharmacogenetics)
  • Pregnancy and lactation
  • Patients with pre-existing blood dyscrasias
  • Patients with severe hepatic impairment or severe renal impairment
  • Treatment with sorivudine or its chemically related analogues, such as brivudine

Drug interactions[edit]

Drugs it is known to interact with includes:[6]

  • Sorivudine or its analogues, such as, brivudine.
  • Allopurinol as it decreases the efficacy of 5-FU.
  • CYP2C9 substrates, including, warfarin and other coumarin-derivatives anticoagulants
  • Phenytoin, as it increases the plasma concentrations of phenytoin.
  • Calcium folinate may enhance the therapeutic effects of capecitabine by means of synergising with its metabolite, 5-FU. It may also induce more severe diarrhoea by means of this synergy.[1]

Pharmacogenetics[edit]

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes capecitabine, 5-fluorouracil and tegafur.[9] 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.[9][10] 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.[10][9] The Clinical Pharmacogenetics Implementation Consortium (CPIC)[9] and the Dutch Pharmacogenetics Working Group (DPWG)[11] both recommend reducing the starting dose by 50% in individuals with partial DPD deficiency, and selecting an alternative drug in those with complete DPD deficiency. The FDA-approved drug label for capecitabine also states that the drug is contraindicated in patients with known DPD deficiency.[4]

Mechanism of action[edit]

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

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FluoropyrimidineActivity_WP1601 go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go to article
|{{{bSize}}}px|alt=Fluorouracil (5-FU) Activity edit|]]
Fluorouracil (5-FU) Activity edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". 

Capecitabine is metabolised to 5-FU which in turn is a thymidylate synthase inhibitor, hence inhibiting the synthesis of thymidine monophosphate (ThMP), the active form of thymidine which is required for the de novo synthesis of DNA and RNA during gene expression.[2]

References[edit]

  1. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  2. ^ a b c "Xeloda (capecitabine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 25 January 2014. 
  3. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.  edit
  4. ^ a b "XELODA (capecitabine) tablet, film coated [Genentech, Inc.]". DailyMed. Genentech, Inc. December 2013. Retrieved 25 January 2014. 
  5. ^ "Capecitabine Teva : EPAR - Product Information" (PDF). European Medicines Agency. Teva Pharma B.V. 10 January 2014. Retrieved 25 January 2014. 
  6. ^ a b c "Capecitabine 150mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Zentiva. 23 December 2013. Retrieved 25 January 2014. 
  7. ^ "NAME OF THE MEDICINE XELODA® Capecitabine" (PDF). TGA eBusiness Services. Roche Products Pty Limited. 5 December 2013. Retrieved 25 January 2014. 
  8. ^ Reddening, swelling, numbness and desquamation on palms and soles
  9. ^ a b c d 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): 640–5. doi:10.1038/clpt.2013.172. PMID 23988873. 
  10. ^ a b Amstutz, U; Froehlich, TK; Largiadèr, CR (September 2011). "Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity.". Pharmacogenomics 12 (9): 1321–36. PMID 21919607. 
  11. ^ Swen, JJ; Nijenhuis, M; de Boer, A; Grandia, L; Maitland-van der Zee, AH; Mulder, H; Rongen, GA; van Schaik, RH; Schalekamp, T; Touw, DJ; van der Weide, J; Wilffert, B; Deneer, VH; Guchelaar, HJ (May 2011). "Pharmacogenetics: from bench to byte--an update of guidelines.". Clinical pharmacology and therapeutics 89 (5): 662–73. PMID 21412232. 

External links[edit]