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

• Published in: Cancer chemotherapy and pharmacology 2003-02, Vol.51 (2), p.167-173
• Main Authors: MARING, Jan Gerard, PIERSMA, Henk, VAN DALEN, Albert, GROEN, Harry J. M, UGES, Donald R. A, DEVRIES, Elisabeth G. E
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Female; Fluorouracil - adverse effects; Fluorouracil - analogs & derivatives; Fluorouracil - pharmacokinetics; Gastrointestinal Neoplasms - pathology; Humans; Liver - physiopathology; Liver Neoplasms - metabolism; Liver Neoplasms - physiopathology; Liver Neoplasms - secondary; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-002-0535-2

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). 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 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. 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). 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.