Plasma concentrations of 5-fluorouracil and F-β-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil

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 m(2), 100 mg day(−1) in those with a BSA of ⩾1.25 m(2) to <1.5 m(2), and 120 mg day(−1) in those with a BSA of ⩾1.5 m(2). Plasma concentrations of 5-FU and F-β-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 728±113 ng h ml(−1) for PVI of 5-FU and 1364±374 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 9465±3225 ng h ml(−1), AUC(0–10 h), as compared with 1725±605 ng h ml(−1) on day 5 of S-1 treatment. The AUC(0–10 h) of uracil on day 5 was 252±60 ng h ml(−1) with PVI of 5-FU and 12 582±3060 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.