Time-dependent pharmacokinetics of 5-fluorouracil and association with treatment tolerability in the adjuvant setting of colorectal cancer

Toni Ibrahim, Antonello Di Paolo, Federica Amatori, Laura Mercatali, Elena Ravaioli, Emanuela Flamini, Emanuele Sacanna, Mario Del Tacca, Romano Danesi, Dino Amadori

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Abstract

The authors evaluated the influence of 5-fluorouracil (5-FU) on treatment tolerability in 81 colorectal cancer patients given adjuvant 5-FU intravenously plus folinic acid for 6 cycles. The pharmacokinetics of 5-FU and its inactive metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) were measured on days 1 and 5 of the first chemotherapy cycle, 5 and 45 minutes after bolus administration. 5-FU clearance was significantly lower on day 5 (62.64 ± 20.16 L/h/m2) than on day 1 (74.83 ± 31.61 L/h/m2). The lower 5-FU clearance values also predicted the side effects during the entire course of chemotherapy. In particular, patients with low clearance values on day 1 had a further reduction in this parameter on day 5, associated with severe toxicities. In conclusion, 5-FU alters its clearance, which could be partly due to a reduction in 5-FDHU biotransformation. These findings have safety implications for poor metabolizers whose drug clearance may fall below the threshold during repeated treatment cycles.

Original languageEnglish
Pages (from-to)361-369
Number of pages9
JournalJournal of Clinical Pharmacology
Volume52
Issue number3
DOIs
Publication statusPublished - Mar 2012

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Fluorouracil
Colorectal Neoplasms
Pharmacokinetics
Therapeutics
Drug Therapy
Leucovorin
Biotransformation
Safety
Pharmaceutical Preparations
dihydrouracil

Keywords

  • 5-Fluorouracil
  • metabolism
  • pharmacokinetics
  • toxicity

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Time-dependent pharmacokinetics of 5-fluorouracil and association with treatment tolerability in the adjuvant setting of colorectal cancer. / Ibrahim, Toni; Di Paolo, Antonello; Amatori, Federica; Mercatali, Laura; Ravaioli, Elena; Flamini, Emanuela; Sacanna, Emanuele; Del Tacca, Mario; Danesi, Romano; Amadori, Dino.

In: Journal of Clinical Pharmacology, Vol. 52, No. 3, 03.2012, p. 361-369.

Research output: Contribution to journalArticle

Ibrahim, Toni ; Di Paolo, Antonello ; Amatori, Federica ; Mercatali, Laura ; Ravaioli, Elena ; Flamini, Emanuela ; Sacanna, Emanuele ; Del Tacca, Mario ; Danesi, Romano ; Amadori, Dino. / Time-dependent pharmacokinetics of 5-fluorouracil and association with treatment tolerability in the adjuvant setting of colorectal cancer. In: Journal of Clinical Pharmacology. 2012 ; Vol. 52, No. 3. pp. 361-369.
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