Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage

J Clin Oncol. 1999 Apr;17(4):1105. doi: 10.1200/JCO.1999.17.4.1105.


Purpose: Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU.

Patients and methods: Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m(2) was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH(2)), were measured before treatment, and the ratio of UH(2) to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH(2) to U and 5-FU metabolic outcome and tolerance.

Results: The UH(2)-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r =.58), (2) 5-FU plasma clearance (r =.639), and (3) individual optimal therapeutic 5-FU dose (r =.65). Toxic side effects were observed only in patients with initial UH(2)-U ratios of less than 1.8. No adverse effects were noted in patients with UH(2)-U ratios of greater than 2.25.

Conclusion: The UH(2)-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Area Under Curve
  • Chi-Square Distribution
  • Chromatography, Liquid
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Female
  • Fluorouracil / adverse effects*
  • Fluorouracil / pharmacokinetics*
  • Humans
  • Leucovorin / administration & dosage
  • Linear Models
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Prospective Studies
  • Uracil / analogs & derivatives*
  • Uracil / blood*


  • Antimetabolites, Antineoplastic
  • dihydrouracil
  • Uracil
  • Leucovorin
  • Fluorouracil