Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokineticswith liver damage induced by bile duct ligation in rats

Hepatic metabolism is the main determinant in the pharmacokinetics of B-flu orouracil (5-FU). Its disposition might be affected with liver dysfunction. In the present study, the influence of liver damage induced by bile duct l igation on dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism, CYP2B, and 5-FU pharmacokinetics were compared in male Sp rague-Dawley rats. After 3 weeks of the ligation in two different groups of animals for in vitro and pharmacokinetic experiments, significant increase s in serum bilirubin level and spleen weight were found in both groups. No significant differences were noted in bilirubin level or spleen weight of t he bile duct ligation group between the two experiment groups. In the in vi tro experiment, DPD activity and protein levels determined by Western blot analysis in the bile duct ligation group were slightly but significantly gr eater than those of a sham-operated group, whereas CYP2B activity and prote in level were significantly reduced. These findings were supported by mRNA levels of CYP2B and DPD. When 40 mg/kg 5-FU was administered i.v. in the ph armacokinetic experiment, no significant differences in pharmacokinetic par ameters were found between the bile duct ligation and sham-operated groups. These results suggested that DPD activity and protein level were maintaine d and that 5-FU pharmacokinetics was not altered in the presence of liver d amage accompanied by a significant reduction in CYP2B activity and protein level, supporting previous clinical studies showing that mild to moderate l iver dysfunction does not affect 5-FU disposition.