Nonlinear pharmacokinetics of 5-fluorouracil in rats.

The effects of dose on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated following intravenous administration of 5-FU at 10, 50, and 100 mg/kg to adult male Sprague-Dawley rats. Six rats were studied at each dose level. The dose-normalized area under the curve (AUC) was significantly higher after administration of 100 mg/kg (1.14 +/- 0.55 mg.h/L/mg; mean +/- SD) than after 50 mg/kg (0.50 +/- 0.18 mg.h/L/mg) or 10 mg/kg (0.43 +/- 0.11 mg.h/L/mg), indicating nonlinear elimination of 5-FU in rats. Dose- and time-average pharmacokinetic parameters were calculated by area/moment analysis. The systemic clearance of 5-FU following administration of 100 mg/kg was significantly lower (1.1 +/- 0.49 L/h/kg) than after 50 mg/kg (2.2 +/- 0.72 L/h/kg) or 10 mg/kg (2.4 +/- 0.67 L/h/kg). There was no significant difference in renal clearance values between the three doses (0.47 +/- 0.26 L/h/kg). However, nonrenal clearance was significantly lower after the 100-mg/kg dose (0.77 +/- 0.2 L/h/kg) than after the 50-mg/kg (1.65 +/- 0.49 L/h/kg) and 10-mg/kg (1.87 +/- 0.75 L/h/kg) doses. There was no significant difference between the steady-state volume of distribution values (0.91 +/- 0.36 L/kg) at the three doses. The lower nonrenal clearance following the 100-mg/kg dose compared with that after the lower doses of 5-FU suggested nonlinear metabolism of 5-FU in rats. A two-compartment pharmacokinetic model with parallel first-order (renal excretion) and Michaelis-Menten elimination from the central compartment was simultaneously fit to mean plasma 5-FU concentration versus time data for the three doses. The maximum volume (Vmax) and Michaelis constant (Km) values averaged (mean +/- SE) 8.3 +/- 2.3 mg/h and 31.6 +/- 11.9 mg/L, respectively. The information obtained in this study will be valuable for the evaluation of prodrugs of 5-FU that are designed to reduce toxicities and to improve oral bioavailability of the anticancer agent.