Abstract. Aims: To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction. Methods: In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50mg, orally) on days1 and 2 and 5-FU (20mg/m2, orally) on day2 following either a 2-h fast or 20min after a standard meal. Treatments were separated by 7days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods. Results: In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6l/h. The mean absorption lag-time was 0.24h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (Cmax) of 5-FU was decreased by 21% and the time to Cmax was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods. Conclusions: Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU Cmax, but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.