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/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.
RCT Entities:
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/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: André B P van Kuilenburg; Peter Häusler; Andreas Schalhorn; Michael W T Tanck; Johannes H Proost; Christoph Terborg; Detlev Behnke; Wolfgang Schwabe; Kati Jabschinsky; Jan Gerard Maring Journal: Clin Pharmacokinet Date: 2012-03-01 Impact factor: 6.447
Authors: Maurice C van Staveren; Barbara Theeuwes-Oonk; Henk Jan Guchelaar; André B P van Kuilenburg; Jan Gerard Maring Journal: Cancer Chemother Pharmacol Date: 2011-05-18 Impact factor: 3.333
Authors: V M Daryani; Y T Patel; M Tagen; D C Turner; A M Carcaboso; J M Atkinson; A Gajjar; R J Gilbertson; K D Wright; C F Stewart Journal: CPT Pharmacometrics Syst Pharmacol Date: 2016-04-14