Capecitabine (Ro 09-1978) is a novel oral fluoropyrimidine carbamate that was rationally designed to generate 5-fluorouracil (5-FU) selectively in tumors. The effect of food on the pharmacokinetics of capecitabine and its metabolites was investigated in 11 patients with advanced colorectal cancer using a two-way cross-over design with randomized sequence. Patients received repeated doses of 666 or 1255 mg/m2 of capecitabine twice daily. On study days 1 and 8, drug was administered following an overnight fast or within 30 min after consumption of a standard breakfast, and serial blood samples were collected. Concentrations of capecitabine and its metabolites [5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), 5-FU, dihydro-5-fluorouracil (FUH2), and alpha-fluoro-beta-alanine (FBAL)] in plasma were determined by high-performance liquid chromatography or liquid chromatography/mass spectroscopy. Intake of food prior to the administration of capecitabine resulted in pharmacokinetic changes of all compounds involved. The extent of these changes, however, varied considerably between the various compounds. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'-DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials.