Clinical Pharmacokinetics of 5-Fluorouracil and Its Metabolites in Plasma, Urine, and Bile

Kinetics of 5-fluorouracil (FUra) and FUra metabolites in plasma and urine were investigated in 10 cancer patients following i.v. bolus administration of 500 mg/m² FUra with 600 μCi of [6-³H]FUra. Biliary excretion was examined in two patients with external biliary catheters. Quantitation of unchanged drug and metabolites was assessed by a highly specific high-performance liquid chromatographic method. FUra plasma levels declined rapidly with an apparent elimination half-life of 12.9 ± 7.3 min. Dihydrofluorouracil was detected within 5 min in most patients, demonstrating rapid catabolism and reached maximum peak levels of 23.7 ± 9.9 μM at approximately 60 min. The apparent elimination half-life of dihydrofluorouracil (61.9 ± 39.0 min) was consistently greater than that of the unchanged drug. The apparent elimination half-lives of the subsequent metabolites α-fluoro-β-ureidopropionic acid and α-fluoro-β-alanine were prolonged with values of 238.9 ± 175.4 min and 1976 ± 358 min, respectively. Approximately 60-90% of the administered dose was excreted in urine within 24 h, primarily as α-fluoro-β-alanine. Biliary excretion accounted for 2-3% of total administered radioactivity. The major fraction of this radioactivity eluted on high-performance liquid chromatography as a previously unrecognized FUra metabolite. Analysis of its structure is currently ongoing in our laboratory. In conclusion, this study provides the first comprehensive analysis of the formation and excretion of FUra metabolites in plasma, urine, and bile following i.v. bolus administration of FUra in humans.