Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model.

Abstract

Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model. Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects. The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p < 0.001). The HC group had a significantly lower liver DPD than the CC group (4.4 ± 1.1mg vs 6.9 ± 1.1mg, p < 0.01). The HC group had a significantly lower ileal villous height than the CC group (253 ± 40μm vs. 318 ± 36μm, p < 0.05). Reduction of the total liver DPD following major hepatectomy caused increased plasma 5-FU levels and 5-FU-associated toxicity.