1. ¹Laboratoire d'Oncopharmacologie, Centre Antoine Lacassagne, Nice, France
2. ²Laboratoire de Biopharmacie, Faculté de Pharmacie, Clermont-Ferrand, France
3. ³Department of Clinical Oncology, Centre René Gauducheau, Nantes, France
4. ⁴Department of Clinical Oncology, Centre Paul Papin, Angers, France

Correspondence: G Milano, (gerard.milano@nice.fnclcc.fr)

Received 23 March 2007; Accepted 12 June 2007; Published online 18 July 2007.

Abstract

Uracil-Ftorafur (UFT) combines the 5-fluorouracil (FU) prodrug tegafur with uracil (at a 1:4 molar ratio), which is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the limiting enzyme of FU catabolism.¹ As a result, sustained FU concentrations are obtained in both plasma and tumor ². UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic ³ and adjuvant ⁴ colorectal cancer treatment. A circadian rhythm for DPD activity has been shown in both human and animal studies, with consequences on FU plasma concentrations in patients receiving FU as a continuous infusion ⁵. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine ⁶ and FU infusions ⁷, suggesting that such schedules may improve the fluoropyrimidine therapeutic index. Molecular mechanisms responsible for the circadian dependence of FU pharmacodynamics include circadian rhythms in thymidylate synthase activity and DNA synthesis, as recently reported ⁸. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported ⁹. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.¹⁰.