Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

Br J Cancer. 2002 Apr 8;86(7):1028-33. doi: 10.1038/sj.bjc.6600208.


5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m(-2) plus 5-fluorouracil 425 mg m(-2). Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve(0-->3h) in the index patient was 24.1 mg h l(-1) compared to 9.8+/-3.6 (range 5.4-15.3) mg h l(-1) in control patients. The 5-fluorouracil clearance was 520 ml min(-1) vs 1293+/-302 (range 980-1780) ml min(-1) in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h(-1)) compared to the six controls (10.3+/-1.6, range 8.0-11.7 nmol mg h(-1)). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Alleles
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Chromatography, High Pressure Liquid
  • Colorectal Neoplasms / drug therapy
  • DNA, Neoplasm / genetics*
  • Dihydrouracil Dehydrogenase (NADP)
  • Female
  • Fluorouracil / adverse effects*
  • Fluorouracil / pharmacokinetics*
  • Humans
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Oxidoreductases / genetics
  • Oxidoreductases / pharmacology*
  • Point Mutation*
  • Polymerase Chain Reaction
  • Sequence Analysis, DNA


  • Antimetabolites, Antineoplastic
  • DNA, Neoplasm
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Leucovorin
  • Fluorouracil