Dose and time dependencies of 5-fluorouracil pharmacokinetics

Objectives: The purpose of this study was to examine the interpatient and i ntrapatient variability of the Michaelis-Menten plasma parameters of 5-fluo rouracil administered according to a schedule combining a bolus of 400 mg/m (2) followed by 22-hour infusion of 600 mg/m(2) for 2 consecutive days. Patients. A pharmacokinetic population approach was used to analyze the dat a from 21 patients with colorectal cancer. Results: The 5-fluorouracil plasma concentrations versus time were best des cribed by a two-compartment model with nonlinear elimination from the centr al compartment. The relationships between the pharmacokinetic parameters an d patient characteristics were tested. On day 1 the mean values (with inter individual variability as expressed by the coefficient of variation) were 1 390 mg . h(-1) (20%), and 5.57 mg . L-1 (22%) for the maximum rate of elimi nation, and the half-saturating plasma concentration. The maximum rate of e limination was positively correlated to the body surface area and the perce ntage of liver involvement by metastatic disease determined by tomodensitom etric examination. The model was successfully tested with independent data sets corresponding to other schedules. The analysis of this intrapatient va riability showed that the half-saturating plasma concentration increased fr om day 1 to day 2, especially in the patients with low lymphocyte cell dihy dropyrimidine dehydrogenase activity. Conclusion: The pharmacokinetic parameters obtained in this study would be useful to predict the 5-fluorouracil plasma concentrations following other schedules of administration of 5-fluorouracil and to study the possible pha rmacokinetic interactions between 5-fluorouracil and other drugs.