title: Extensive hepatic replacement due to liver metastases has no effect on 5-fluorouracil pharmacokinetics.
abstract: 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.
authors.affiliation: Department of Pharmacy, Diaconessen Hospital Meppel and Bethesda Hospital Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands. maring@diacmeppel.nl
authors.forename: Jan Gerard
authors.initials: JG
authors.lastname: Maring
authors.forename: Henk
authors.initials: H
authors.lastname: Piersma
authors.forename: Albert
authors.initials: A
authors.lastname: van Dalen
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Donald R A
authors.initials: DR
authors.lastname: Uges
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: De Vries
mesh_terms: 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
chemical_list: C019389:5-fluorodihydrouracil; D005472:Fluorouracil