Pharmacokinetic Study of S-1, a Novel Oral Fluorouracil Antitumor Drug

• Published in: Clinical cancer research 1999-08, Vol.5 (8), p.2000-2005
• Main Authors: HIRATA, K, HORIKOSHI, N, TAGUCHI, T, SHIRASAKA, T, AIBA, K, OKAZAKI, M, DENNO, R, SASAKI, K, NAKANO, Y, ISHIZUKA, H, YAMADA, Y, UNO, S
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - urine; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - urine; Chemotherapy; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - urine; Drug Combinations; Drug Evaluation; Female; Humans; Male; Medical sciences; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - urine; Oxonic Acid - adverse effects; Oxonic Acid - blood; Oxonic Acid - pharmacokinetics; Oxonic Acid - urine; Pharmacology. Drug treatments; Pyridines - adverse effects; Pyridines - blood; Pyridines - pharmacokinetics; Pyridines - urine; Stomach Neoplasms - blood; Stomach Neoplasms - drug therapy; Stomach Neoplasms - urine; Tegafur - adverse effects; Tegafur - blood; Tegafur - pharmacokinetics; Tegafur - urine
• ISSN: 1078-0432; 1557-3265

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/m 2 /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/m 2 /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 m 2 , 80 mg/body/day; for 1.25 m 2 ≤ BSA < 1.5 m 2 , 100 mg/day; and for 1.5 m 2 ≤ 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/m 2 (31.7–39.7 mg/m 2 ). Pharmacokinetic parameters of plasma 5-FU were as follows: C max , 128.5 ± 41.5 ng/ml; T max , 3.5 ± 1.7 h; AUC 0–14 , 723.9 ± 272.7 ng · 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.