This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peters, G. J. Articles by Schellens, J. H. M. Search for Related Content PubMed PubMed Citation Articles by Peters, G. J. Articles by Schellens, J. H. M.

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

Departments of ¹ Medical Oncology and ² Clinical Chemistry, VU University Medical Center, Amsterdam; ³ New Drug Development Organization Oncology, Amsterdam; ⁴ European Organization for Research and Treatment of Cancer–New Drug Development Group, Brussells, Belgium; and ⁵ Netherlands Cancer Institute, Amsterdam, the Netherlands

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/m² 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 x min; and T_1/2, 104 min. Fasting decreased Tmax of FT, 5FU, CDHP, and oxonic acid significantly (P < 0.006) and increased the Cmax (P < 0.013). The food/fast ratio for the AUC of FT was not different, which for 5FU was 0.84 (P = 0.041), for CDHP was 0.89 (P = 0.191), for oxonic acid was 0.48 (P < 0.0005), and for cyanuric acid, the breakdown product of oxonic acid, was 5.1 (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.

This article has been cited by other articles:

				J. A. Ajani, J. Faust, K. Ikeda, J. C. Yao, H. Anbe, K. L. Carr, M. Houghton, and P. Urrea Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma J. Clin. Oncol., October 1, 2005; 23(28): 6957 - 6965. [Abstract] [Full Text] [PDF]