PHARMACOKINETICS OF 5-FLUOROURACIL AFTER INTRAVENOUS-INFUSION OF 5-FLUOROURACIL-ACETIC ACID-HUMAN SERUM-ALBUMIN CONJUGATES TO RABBITS

The pharmacokinetics of 5-fluorouracil (5-FU) was compared after 30 min intravenous infusion of the same dose (20 mg/kg as 5-FU) of 5-FU (treatment I), 5-FU-acetic acid (5-FU-AA, treatment II) and 5-FU-AA-human serum albumin conjugates (5-FU-AA-HSA, treatment III) to rabbits. After post-infusion, plasma levels of 5-FU declined rapidly with a mean half-life of 8.0 min from treatment I, however, they were not detected until 10-50 min and the mean plasma concentration of 1 mu-g/ml was maintained from 3 to 24 h for treatment III. It might be possible to maintain constant plasma concentrations of 5-FU for a long period of time by 30 min infusion of 5-FU-AA-HSA conjugates instead of tedious time-consuming infusion of 5-FU. The mean values of 24 h AUC (623 vs 1290-mu-g min ml-1) were significantly higher from treatment III than that from treatment I. 5-FU was not detected from treatment II nor 5-FU-AA from treatment III in both plasma and urine samples. In treatment II, 5-FU-AA was eliminated rapidly with a mean apparent terminal half-life of 18.7 min based on urinary excretion rate data. 5-FU was not detected in brain after 30 min intravenous infusion of both 5-FU and 5-FU-AA, however, significant amounts of 5-FU were found in brain after administration of 5-FU-AA-HSA conjugates. The in vitro release of 5-FU from 5-FU-AA-HSA conjugates was increased in the presence of protease or liver homogenates, however, 5-FU was not detected for up to 24 h incubation of 5-FU-AA with the various solutions.