1. ¹Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2. ²Taiho Pharmaceutical Co., Ltd. Pharmacokinetics Research Lab, 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan

Correspondence: Y Yamada, E-mail: yayamada@ncc.go.jp

Received 25 November 2002; Revised 3 June 2003; Accepted 29 June 2003.

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 m², 100 mg day^-1 in those with a BSA of 1.25 m² to <1.5 m², and 120 mg day^-1 in those with a BSA of 1.5 m². Plasma concentrations of 5-FU and F--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 728113 ng h ml^-1 for PVI of 5-FU and 1364374 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 94653225 ng h ml^-1, AUC_0–10 h, as compared with 1725605 ng h ml^-1 on day 5 of S-1 treatment. The AUC_0–10 h of uracil on day 5 was 25260 ng h ml^-1 with PVI of 5-FU and 12 5823060 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.