The Effect of Food on the Pharmacokinetics of S-1 after Single Oral Administration to Patients with Solid Tumors

Purpose: The purpose is to determine the effect of food on the bioavailability of S-1, an oral formulation of the 5-fluorouracil (5FU) prodrug Ftorafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), a dihydropyrimidine dehydrogenase inhibitor, and oxonic acid (an inhibitor of 5FU phosphoribosylation in normal gut mucosa) in a molar ratio of 1:0.4:1. Experimental Design: Eighteen patients received a single dose of S-1 of 35 mg/m 2 with (535–885 kcal) or without food in a crossover study design: in arm A without breakfast on day −7 and with breakfast on day 0 and in arm B the reversed sequence. Blood samples were taken before and after S-1 administration. This food effect was evaluated according to the Food and Drug Administration guidelines using log-transformed data. Results: Pharmacokinetic parameters for 5FU without breakfast were as follows: Tmax, 107 min; Cmax, 1.60 μm; area under the plasma concentration-time curve (AUC) 441 μm × min; and T 1/2 , 104 min. Fasting decreased Tmax of FT, 5FU, CDHP, and oxonic acid significantly ( P P P = 0.041), for CDHP was 0.89 ( P = 0.191), for oxonic acid was 0.48 ( P P = 0.019). Accumulation of uracil, indicative for dihydropyrimidine dehydrogenase inhibition, was not affected, as well as the T 1/2 of FT, 5FU, CDHP, and oxonic acid. Evaluation of the log-transformed data demonstrated that the 90% confidence interval for the food/fast ratio for the Cmax and AUC of FT, 5FU, CDHP, and uracil were within 70–143% and 80–125%, respectively, indicating no food effect. Only for oxonic acid and cyanuric acid were these values outside this interval. Conclusions: Food intake affected only the pharmacokinetics of the S-1 constituent oxonic acid but not of FT, CDHP, and 5FU. Because oxonic acid is included to protect against gastrointestinal toxicity, this observation might affect the gastrointestinal toxicity and thus the efficacy of S-1.