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

Abstract

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.

Effect of Metabolic Inhibitors on the Hepatic Disposition of 5-Fluorouracil after Application to the Rat Liver Surface

“…[13][14][15][16][17][18][19][20]23) Because 5-FU is mostly catabolized and inactivated by DPD, 28) we expected that combining DPD inhibitors enable us to increase 5-FU availability at the admin- istration site. In this study, we chose gimeracil and uridine as candidates for promising DPD inhibitors that can be applied to the rat liver surface.…”

“…The applied dose of 5-FU was set according to our previous study. 23) A piece of aluminum foil was placed on the top of the diffusion cell to prevent evaporation.…”

“…19,20) We have also investigated other organs as an administration route of 5-FU. 21,22) Although viscous additives to 5-FU solution improved site-selective accumulation of 5-FU, 23) the increase in 5-FU concentration at the application site was not large enough.…”

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

“…previously developed a direct route of application to the liver surface and found it to be a useful method for drug targeting (Nishida, Sato, Sasaki, & Nakamura, ; Nishida, Sato, Sasaki, & Nakamura, ; Nishida, Sato, Sasaki, & Nakamura, ; Nishida et al ., ; Nishida et al ., ). Furthermore, liver surface application could achieve the site‐selective delivery of an anticancer drug, 5‐fluorouracil (5‐FU), to the liver (Kodama et al ., ; Kodama et al ., ). However, there remain several problems to be overcome, including poor penetration into tumor tissue, short retention and low availability for time‐dependent anticancer drugs, such as 5‐FU.…”

Influence of Liver Intoxication by Carbon Tetrachloride or D-Galactosamine on Absorption of Fluorescein Isothiocyanate-Dextran-10 and Other Marker Compounds with Different Molecular Weights from the Rat Liver Surface

“…In previous studies, we have shown that application of low-molecular-weight compounds such as phenolsulfonphthalein and 5-fluorouracil to the liver surface enhanced drug delivery to desired sites in the liver. [1][2][3][4][5] The absorbability of macromolecules as well as their targeting efficacy were also improved. 2,5) The liver surface application might be useful for reduction of side effect and improve the effect of drugs because drugs administered to liver surface were selectivity accumulate into applied site.…”