Extensive hepatic replacement due to liver metastases has no effect on 5-fluorouracil pharmacokinetics.
OBJECTIVE
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/m(2) per day plus 5-FU 425 mg/m(2) 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.
Maring
Jan Gerard
JG
Department of Pharmacy, Diaconessen Hospital Meppel and Bethesda Hospital Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands. maring@diacmeppel.nl
Piersma
Henk
H
van Dalen
Albert
A
Groen
Harry J M
HJ
Uges
Donald R A
DR
De Vries
Elisabeth G E
EG
D000368:Aged; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005770:Gastrointestinal Neoplasms / Q000473:pathology; D006801:Humans; D008099:Liver / Q000503:physiopathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000556:secondary*; D008297:Male; D008875:Middle Aged
C019389:5-fluorodihydrouracil; D005472:Fluorouracil