Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil

Br J Cancer. 2003 Sep 1;89(5):816-20. doi: 10.1038/sj.bjc.6601224.

Abstract

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg m(-2) day(-1) for 5 days. After a washout period of 9 days, the patients received two divided doses daily for 28 days. S-1 was administered orally at about 0900 and 1900 hours. The daily dose of S-1 in terms of tegafur was 80 mg day(-1) in patients with a body surface area (BSA) of <1.25 m(2), 100 mg day(-1) in those with a BSA of >or=1.25 m(2) to <1.5 m(2), and 120 mg day(-1) in those with a BSA of >or=1.5 m(2). Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition (pharmacodynamic analysis) in the same patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC(0-10 h)) of 5-FU on day 5 was 728+/-113 ng h ml(-1) for PVI of 5-FU and 1364+/-374 ng h ml(-1) for S-1. The median 5-FU PVI : S-1 ratio of the AUC(0-10 h) of 5-FU was 1.9. The AUC(0-10 h) of FBAL on day 5 of PVI of 5-FU was 9465+/-3225 ng h ml(-1), AUC(0-10 h), as compared with 1725+/-605 ng h ml(-1) on day 5 of S-1 treatment. The AUC(0-10 h) of uracil on day 5 was 252+/-60 ng h ml(-1) with PVI of 5-FU and 12 582+/-3060 ng h ml(-1) with S-1. The AUC(0-10 h) of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / blood
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Area Under Curve
  • Dihydrouracil Dehydrogenase (NADP)
  • Drug Combinations
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics
  • Fluorouracil / administration & dosage*
  • Fluorouracil / blood*
  • Fluorouracil / pharmacokinetics
  • Gastrointestinal Neoplasms / drug therapy
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Oxidoreductases / drug effects
  • Oxidoreductases / metabolism
  • Oxonic Acid / administration & dosage*
  • Pyridines / administration & dosage*
  • Tegafur / administration & dosage*
  • Uracil / blood
  • beta-Alanine / blood*
  • beta-Alanine / pharmacokinetics

Substances

  • Antimetabolites, Antineoplastic
  • Drug Combinations
  • Enzyme Inhibitors
  • Pyridines
  • beta-Alanine
  • S 1 (combination)
  • Tegafur
  • Uracil
  • Oxonic Acid
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil