Extensive hepatic replacement due to liver metastases has no effect on 5-fluorouracil pharmacokinetics

Abstract

Purpose. The influence of liver metastases on the pharmacokinetics of 5-fluorouracil (5-FU) and its metabolite 5,6-dihydrofluorouracil (DHFU) was studied in patients with liver metastases from gastrointestinal cancer (n=16) and compared with a control group of patients with nonmetastatic gastrointestinal cancer (n=18).

Methods. Patients were assigned to two different groups based on the presence of liver metastases. The percentage of hepatic replacement was determined with CT and ultrasonography and classified as <25%, 25–50% or >50% of the total liver volume. Chemotherapy consisted of leucovorin 20 mg/m² per day plus 5-FU 425 mg/m² per day, both for 5 days. Blood sampling was carried out on the first day of the first chemotherapy cycle. 5-FU and DHFU were quantified in plasma by HPLC. A four-compartment parent drug-metabolite model with nonlinear Michaelis-Menten elimination from the central compartment of the parent drug (5-FU) was applied to describe 5-FU and DHFU pharmacokinetics.

Results. No effect of liver metastases on 5-FU clearance was observed. The effects of 18 covariables on pharmacokinetic parameters were also studied in a univariate correlation analysis. Body surface area was positively correlated with the distribution volume of 5-FU in the central compartment and with V_max (r=0.65 and r=0.54, respectively).

Conclusions. There is no need for dose adjustment of 5-FU as a standard procedure in patients with liver metastases and mild to moderate elevations in liver function tests.