title: Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug.
abstract: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.
authors.affiliation: Department of Surgery I, Sapporo Medical University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hirata
authors.forename: N
authors.initials: N
authors.lastname: Horikoshi
authors.forename: K
authors.initials: K
authors.lastname: Aiba
authors.forename: M
authors.initials: M
authors.lastname: Okazaki
authors.forename: R
authors.initials: R
authors.lastname: Denno
authors.forename: K
authors.initials: K
authors.lastname: Sasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Nakano
authors.forename: H
authors.initials: H
authors.lastname: Ishizuka
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Uno
authors.forename: T
authors.initials: T
authors.lastname: Taguchi
authors.forename: T
authors.initials: T
authors.lastname: Shirasaka
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000652:urine; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000652:urine; D004338:Drug Combinations; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D010094:Oxonic Acid / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy / Q000652:urine; D005641:Tegafur / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid