Dose-dependency in local disposition of 5-fluorouracil under non-steady-state condition in rat liver
✍ Scribed by Mitsuo Higashimori; Kiyoshi Yamaoka; Terumichi Nakagawa
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 265 KB
- Volume
- 89
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
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 g 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.