Plasma concentrations of 5-fluorouracil (FU) and its primary catabolite, 5', 6'-dihydro-5-fluorouracil (DHFU) were measured using gas-liquid chromatography after single-dose therapy with 7.2-14.4 mg/kg. Because of the limited sensitivity of the assay for drug levels in plasma, the urinary excretion of FU and metabolites was investigated using an ion-specific electrode after either a single bolus (7.0-9.6 mg/kg) or multiple-dose therapy (6.4-7.4 mg/kg/day). Half-life values for the elimination of FU from plasma (mean, 123.5 min) were greater in each patient than for the catabolite (mean, 109.2 min). Values of the area under the curve for FU profiles varied between patients (mean +/- SE, 12.7 +/- 1.9 micrograms X h/ml) by comparison with the relatively constant values for curves of DHFU concentrations (mean +/- SE, 2.8 +/- 0.15 micrograms X h/ml). In pharmacokinetic profiles of urinary excretion a transient phase of convex shape was apparent after 80%-98% of single doses of FU was excreted. Half-lives for the elimination of FU in urine were 2.6-5.9 h, which increased to 18-44 h on multiple dosing. The results demonstrate saturation in the elimination of FU after therapeutic doses, and are consistent with the proposal that reduction of FU to DHFU provides the rate-limiting step.