Altered plasma kinetics of 5-FU at high dosage in rat and man.

To provide a model for pharmacokinetic studies in patients administered high iv doses of 5-FU after allopurinol or other modifiers of toxicity, rats were given radioactive 5-FU as an iv bolus. At a dose of 50 mg/m2 only 16% of circulating radioactivity was identified as 5-FU after 30 minutes, whereas greater than 90% of radioactivity was 5-FU when rats were given a 1800-mg/m2 dose. This 36-fold increase in 5-FU dose was associated with a greater than 150-fold increase in the 30-minute plasma concentration of 5-FU (0.02-3.3 mM). In patients, it was possible to increase the maximum tolerated dose of 5-FU given as a weekly rapid iv bolus from 800 to 1700 mg/m2 when a 3-day course of allopurinol (900 mg/day orally) preceded 5-FU administration. A dose-dependent increase in the apparent half-life of 5-FU in the plasma was observed and plasma concentrations at 30 minutes were as high as 500 microM after a 1600-mg/m2 dose of the drug.