Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

A. Di Paolo, R. Danesi, A. Falcone, L. Cionini, F. Vannozzi, G. Masi, G. Allegrini, E. Mini, G. Bocci, P. F. Conte, M. Del Tacca

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Previous work demonstrated that 5-fluorouracil (5-FU) metabolism is a critical factor for treatment tolerability. In order to study the predictivity of pharmacokinetics with respect to the occurrence of 5-FU toxicity, this study investigates the relationship between the pharmacokinetics of 5-FU and its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMNC) and treatment tolerability. Patients and methods: Pharmacokinetics and metabolism of 5-FU and activity of DPD in PBMNC were examined in 110 colorectal cancer patients given adjuvant 5-FU 370 mg/m2 plus L-folinic acid 100 mg/m2 for five days every four weeks. Drug levels were examined by HPLC, while toxicities were graded according to WHO criteria. Results: DPD activity in patients with mild toxicities (WHO grade ≤ 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein, while in five patients with grade 3-4 gastrointestinal toxicity, DPD ranged from low to normal values (range 31.12-182.37 pmol/min/mg of protein). In these patients, 5-FU clearance (CL) was lower (range 14.12-25.17 l/h/m2), and the area under the curve (AUC) was higher (range 14.70-26.20 h × μg/ml) than those observed in 84 patients with mild toxicities (CL, 56.30 ± 3.60 l/h/m2; AUC, 7.91 ± 0.44 h × μg/ml). The severity of adverse events was associated with increased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and 5-FDHU pharmacokinetics were not related to DPD activity. Conclusion: This study shows that DPD activity in PBMNC is unrelated to 5-FU/5-FDHU disposition and patients with severe toxicity display marked pharmacokinetic alterations while a reduction of DPD activity may not occur.

Original languageEnglish
Pages (from-to)1301-1306
Number of pages6
JournalAnnals of Oncology
Volume12
Issue number9
DOIs
Publication statusPublished - 2001

Keywords

  • 5-fluorouracil
  • DPD
  • Metabolism
  • Pharmacokinetics
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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