Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects
Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects
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DOI：
10.1248/bpb.31.1049
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发表时间：
2008-05-01
影响因子：
2
通讯作者：
Nishida, Koyo
中科院分区：
文献类型：
--
作者：
Kodama, Yukinobu;Fumoto, Shintaro;Nishida, Koyo
本研究旨在阐明5-氟尿嘧啶(5-FU)在大鼠肝脏表面的吸收和分布特征，以探讨其减轻全身副作用的可能性。采用圆柱形扩散池将5-FU应用于肝脏表面。约69%的剂量在360min内被吸收。5-FU在扩散池中的残留量变化符合一级动力学规律。此外，包括5-FU在内的几种化合物的表观渗透系数P-APP与分子量平方根的倒数之间也存在线性关系。5-FU的P-APP预测值与实验值吻合较好。给药后360分钟，5-FU血药浓度较低(1.2mU/ml)。跟随静脉注射。给药后，5-FU迅速从血浆中排出，120min后检测不到。在组织分布分析中，将肝脏分为三个部位：扩散细胞附着部位下区域(部位1)、不包括部位1的处理叶(部位2)和未处理的叶(部位3)。静脉给药后，5-FU主要分布在肾脏，肝脏的浓度明显低于肾、脾、心。应用于肝表面后，5-FU主要分布在第一部位，在其他部位或其他组织中未检测到。因此，这些结果表明，5-FU在肝脏表面应用的全身副作用可能会减少。
The present study was undertaken to elucidate the absorption and distribution characteristics of 5-fluorouracil (5-FU) after its application to the liver surface in rats to examine the possibility of reducing the systemic side effects of this agent. 5-FU was applied to the surface of the liver by employing a cylindrical diffusion cell. Approximately 69% of the dose was absorbed in 360 min. The time course of the change in the amount of 5-FU remaining in the diffusion cell obeyed first-order kinetics. Also, a linear relationship was observed between the apparent permeability coefficient, P-app, and the reciprocal of the square root of the molecular weight of several compounds including 5-FU. The estimated P-app value of 5-FU was in good agreement with the experimental value. The plasma concentration of 5-FU was low (< 1.2 mu g/ml) until 360 min after the application. Following i.v. administration, 5-FU was rapidly eliminated from the plasma and could not be detected at 120 min. In the analysis of tissue distribution, the liver was divided into three sites; the region under the diffusion cell attachment site (site 1), the treated lobe excluding site 1 (site 2), and untreated lobes (site 3). After being administered i.v., 5-FU mainly distributed in the kidney, and the concentration in the liver was significantly lower than that in kidney, spleen, or heart. After its application to the liver surface, however, 5-FU preferentially distributed at site 1, and was not detected at the other sites or in other tissues. Thus, these results suggested the possibility of a reduction in the systemic side effect of 5-FU on its application to the liver surface.