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

Department of Surgery I, Sapporo Medical University, Sapporo 060-8556 [K. H., M. O., R. D., K. S.]; Chemotherapy Cancer Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 170-8455 [N. H., K. A., Y. N., H. I., Y. Y., S. U.]; Japan Society for Cancer Chemotherapy, Osaka 550-0002 [T. T.]; and Institute for Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Co., Ltd., Tokyo 101-0054 [T. S.], Japan

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 BSA < 1.5 m², 100 mg/day; and for 1.5 m² 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: 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.

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