Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients

Pharmacol Res. 2004 Aug;50(2):173-9. doi: 10.1016/j.phrs.2004.01.006.


5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Area Under Curve
  • Chromatography, High Pressure Liquid / methods
  • Colonic Neoplasms / blood
  • Colonic Neoplasms / drug therapy*
  • Drug Administration Schedule
  • Drug Evaluation / methods
  • Female
  • Floxuridine / analogs & derivatives
  • Floxuridine / blood
  • Floxuridine / chemistry
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / blood
  • Fluorouracil / chemistry
  • Fluorouracil / metabolism*
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use*
  • Humans
  • Infusions, Intravenous
  • Injections, Intravenous
  • Kinetics
  • Leucovorin / blood
  • Leucovorin / pharmacology
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Uridine / analogs & derivatives*
  • Uridine / blood
  • Uridine / chemistry


  • Floxuridine
  • 5-fluorouridine
  • 5-fluorodihydrouracil
  • Leucovorin
  • Fluorouracil
  • Uridine