Dose-dependency in local disposition of 5-fluorouracil under non-steady-state condition in rat liver

Dose-dependency in local disposition of 5-fluorouracil (5-FU) was evaluated using the rat liver in the once-through perfusion system under the non-steady-state condition. A curve-fitting program based on Finite Element Method, MULTI(FEM), was adopted to evaluate the capacity-limited elimination in the hepatic local disposition of 5-FU, which is described by a nonlinear dispersion model with a pulse input. The dose of 5-FU was increased from 10.4 to 208 microg for rat livers at five dose levels. Two nonlinear models, two-compartment dispersion models with Michaelis-Menten elimination from the central compartment or from the peripheral compartment, were employed for comparison. The hepatic recovery ratio, F(H), increased from 13.1% to 68.3% and the mean transit time, t(H), increased from 5.1 to 13.1 s with an increase in the dose. It was found that the hepatic local disposition of 5-FU was well represented by the peripheral elimination model. V(max) and K(m) in the model with peripheral Michaelis-Menten elimination were estimated to be 9.04 mg/h and 2.88 mg/L, respectively. V(max) estimated by the present investigation in situ was about seven times greater than that in vitro, whereas K(m) in situ was close to that in vitro. This result suggests that the elimination activity by the hepatocytes in vitro may be lowered, compared with that in situ.