Influence of vasomodulators and tumor transplantation on the disposition of 5-fluorouracil after application to the liver surface in rats.

This study investigated the effect of epinephrine (a vasoconstrictor) and hydralazine (a vasodilator) on the hepatic disposition of 5-fluorouracil (5-FU) after application to the surface of the liver in rats. Normal livers were compared with a Walker 256 carcinoma cell tumor model. A cylindrical diffusion cell was attached to the liver surface. 5-Fluorouracil was added into the diffusion cell in combination with vasomodulators or after pretreatment with epinephrine. After selected treatment times, the 5-FU concentrations were assayed at three sites in the excised livers. The 5-FU concentration in the region under the cell attachment site (site 1) was significantly higher after concomitant application of 5-FU and epinephrine, compared with 5-FU alone, and increased in an epinephrine dose-dependent manner. On the other hand, preferential distribution of 5-FU at site 1 was not seen when applied in combination with hydralazine. After 10 min of epinephrine pretreatment, the concentration of 5-FU at site 1 was approximately two times higher than that for the control. Furthermore, the 5-FU concentration at site 1 of the tumor model was greatly increased compared with the normal liver. These results suggest that application of epinephrine to the liver surface might enhance the accumulation of 5-FU at the desired target site.

Effect of viscous additives on the absorption and hepatic disposition of 5-fluorouracil (5-FU) after application to liver surface in rats.

Objectives The aim was to study the effect of viscous additives on the absorption and hepatic disposition of 5-fluorouracil (5-FU) after application to the liver surface in rats. Methods 5-FU solution with or without viscous additives was applied to the rat liver surface with a cylindrical diffusion cell. Then, blood and the remaining solution in the diffusion cell were collected at selected times, followed by excision of the liver. The excised liver was divided into three sites and assayed for 5-FU content. Key findings The absorption rate of 5-FU from the liver surface was decreased in the presence of carboxymethylcellulose sodium (CMC-Na) and polyvinyl alcohol (PVA) as compared with the control. The k(a) values of PVA 15% and CMC-Na 1% were reduced to about 80 and 67% of the control. The maximum plasma concentration of 5-FU was decreased by incorporation of viscous additives. The 5-FU concentration at the diffusion cell attachment site of the liver (site 1) plateaued at 180 min in the absence of viscous additives. On the other hand, the concentration of 5-FU at site 1 increased in a time-dependent manner until 360 min in the presence of viscous additives. Conclusion Viscous additives might be useful for retaining drugs at their application site and controlling the rate of absorption from the liver surface.