title: 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.
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.
authors.affiliation: Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. yayamada@ncc.go.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.forename: K
authors.initials: K
authors.lastname: Muro
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Y
authors.initials: Y
authors.lastname: Shimada
authors.forename: K
authors.initials: K
authors.lastname: Shirao
authors.forename: S
authors.initials: S
authors.lastname: Nagayama
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D042943:Dihydrouracil Dehydrogenase (NADP); D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D010094:Oxonic Acid / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D005641:Tegafur / Q000008:administration & dosage*; D014498:Uracil / Q000097:blood; D015091:beta-Alanine / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011725:Pyridines; D015091:beta-Alanine; C079198:S 1 (combination); D005641:Tegafur; D014498:Uracil; D010094:Oxonic Acid; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil