Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug

S-l is a novel oral fluorouracil antitumor drug that combines three pharmac ological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine de hydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gast rointestinal toxicity. Phase I and early Phase II clinical trials have alre ady 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 th e pharmacokinetics of 5-FU, intact FT, CDHP, and Ore, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Tw elve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis wa s conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-l for each patient was d etermined 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) less than or equal to BSA < 1.5 m(2), 100 mg/day; and for 1.5 m(2) less than or equal to BSA, 120 mg/day, F or single administration, half of the standard dose was used. For 28-day co nsecutive 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; an d T-1/2, 1.9 +/- 0.4 h. In the 28 day consecutive regimen, there were no fl uctuations in pharmacokinetics nor any drug accumulation. Because the pharm acokinetics of orally administered S-1 is almost similar to that of continu ous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' qual ity of life.