Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile

Cancer Chemother Pharmacol. 2009 May;63(6):1177-80. doi: 10.1007/s00280-008-0889-1. Epub 2008 Dec 24.

Abstract

We report here the case of a 19-year-old female patient who suffered from extremely severe toxicities (G4 mucitis, fever, diarrhea, alteration of general state) while undergoing low-dose capecitabine treatment for her metastatic corticosurrenaloma. The severe toxicities stopped as soon as treatment was suspended. Interestingly, this patient was not deficient in DPD, a pharmacogenetic syndrome usually associated with increased risk of developing severe/lethal toxicities in patients undergoing fluoropyrimidine therapy, and she had been treated previously with 5-FU with a good tolerance. We then hypothesized that cytidine deaminase (CDA) extensive phenotype could be responsible for the severe toxicities observed with capecitabine. CDA is affected by genetic polymorphism, with subsequent acquisition of either deficient or extensive metabolizer profile. Phenotypic investigations confirmed that CDA activity in this patient was +180% higher than the ones usually recorded in the general population. This strongly suggests that the extensive activation of triple-prodrug capecitabine could have occurred in this patient, resulting in overexposure to 5-FU and its cytotoxic metabolites eventually. This case report suggest for the first time that severe toxicities with a capecitabine-containing protocol could be, at least in part, linked with an extensive-CDA syndrome. The case reported here suggests therefore that besides DPD, screening for CDA activity could be of interest to ensure a better safety in the handling of oral capecitabine at the bedside.

Publication types

  • Case Reports

MeSH terms

  • Adrenal Cortex Neoplasms / drug therapy
  • Adrenal Cortex Neoplasms / enzymology
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / therapeutic use
  • Capecitabine
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / therapeutic use
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / pharmacokinetics
  • Fluorouracil / therapeutic use
  • Humans
  • Metabolic Clearance Rate
  • Polymorphism, Genetic
  • Young Adult

Substances

  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • Capecitabine
  • Cytidine Deaminase
  • Fluorouracil