title: Chronopharmacokinetics of oral tegafur and uracil in colorectal cancer patients.
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. As a result, sustained FU concentrations are obtained in both plasma and tumor. UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic and adjuvant 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. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine and FU infusions, 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. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.
authors.affiliation: Laboratoire d'Oncopharmacologie, Centre Antoine Lacassagne, Nice, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: J-M
authors.initials: JM
authors.lastname: Cardot
authors.forename: E
authors.initials: E
authors.lastname: François
authors.forename: N
authors.initials: N
authors.lastname: Renée
authors.forename: J-Y
authors.initials: JY
authors.lastname: Douillard
authors.forename: E
authors.initials: E
authors.lastname: Gamelin
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019454:Chronotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018592:Cross-Over Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D014498:Uracil / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D005641:Tegafur; D014498:Uracil; D005472:Fluorouracil