|Systematic (IUPAC) name|
|Protein binding||< 60%|
|Metabolism||Hepatic, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active fluorouracil|
|Excretion||Renal (95.5%), faecal (2.6%)|
|Molecular mass||359.35 g/mol|
|(what is this?)|
Capecitabine (INN) // (Xeloda, Roche) is an orally-administered chemotherapeutic agent used in the treatment of numerous cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil (5-FU) in the body.
- 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)
- Very common (>10% frequency)
Notes on adverse effects:
- 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
Drugs it is known to interact with includes:
- 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.
The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes capecitabine, 5-fluorouracil and tegafur. 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. 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. The FDA-approved drug label for capecitabine states that the drug is contraindicated in patients with known DPD deficiency.
Mechanism of action
Click on genes, proteins and metabolites below to link to respective articles. [§ 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.
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- Reddening, swelling, numbness and desquamation on palms and soles
- 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.
- 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.