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Summary Background: This study was performed to evaluate the pharmacokinetics, bioequivalence, and feasibility of a combined oral formulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc., Research Triangle Park, North Carolina), an inactivator of dihydropyrimidine dehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FU formulation oral dosing form is to simplify treatment with these agents, which has been performed using separate dosing forms, and decrease the probability of severe toxicity and/or suboptimal therapeutic results caused by inadvertently high or conversely insufficient 5-FU dosing. Patients and methods: The trial was a randomized, threeway crossover bioequivalence study of three oral dosing forms of eniluracil/5-FU tablets in adults with solid malignancies. Each period consisted of two days of treatment and a five- to seven-day washout phase. Eniluracil at a dose of 20 mg, which results in maximal DPD inactivation, was administered twice daily on the first day and in the evening on the second day of each of the three treatments. On the morning of the second day, all patients received a total eniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as either separate tablets (treatment A) or combined eniluracil/5-FU tablets in two different strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of 10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment Q). The pharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinary excretion of eniluracil, 5-FU, uracil, and a-fluoro-(3-alanine (FBAL), were studied. To determine the bioequivalence of the combined eniluracil/5-FU dosing forms compared to the separate tablets, an analysis of variance on pharmacokinetic parameters reflecting eniluracil and 5-FU exposure was performed. Results: Thirty-nine patients with advanced solid malignancies had complete pharmacokinetic studies performed during treatments A, B, and C. The pharmacokinetics of eniluracil and 5-FU were similar among the three types of treatment. Both strengths of the combined eniluracil/5-FU dosing form and the separate dosing forms were bioequivalent. Mean values for terminal half-life, systemic clearance, and apparent volume of distribution for oral 5-FU during treatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and 5O.7/51.5/5O.0 liters, respectively. The intersubject coefficient of variation for pharmacokinetic variables reflecting 5-FU exposure and clearance in treatments ranged from 23% to 33%. The urinary excretion of unchanged 5-FU over 24 hours following treatments A, B, and C averaged 52.2%, 56.1%, and 50.8% of the administered dose of 5-FU, respectively. Parameters reflecting DPD inhibition, including plasma uracil and urinary FBAL excretion following treatments A, B, and C were similar. Toxicity was generally mild and similar following all three types of treatments. Conclusions: The pharmacokinetics of 5-FU and eniluracil were similar and met bioequivalence criteria following treatment with the separate oral formulations of 5-FU and eniluracil and two strengths of the combined formulation. The availability of a combined eniluracil/5-FU oral dosing form will likely simplify dosing and decrease the probability of severe toxicity or suboptimal therapeutic results caused by an inadvertent 5-FU overdose or insufficient 5-FU dosing in the case of separate oral formulations, thereby enhancing the overall feasibility and therapeutic index of oral 5-FU therapy.