Pharmacokinetics of 5-fluorouracil and its catabolites determined by 19F nuclear magnetic resonance spectroscopy for a patient on chronic hemodialysis.
5-fluorouracil (5-FU), widely used for chemotherapy of colorectal carcinoma, requires intracellular anabolic conversion to cytotoxic nucleotides and exhibits a narrow therapeutic range with dose-dependent and concentration-dependent effects. 5-FU undergoes extensive metabolic degradation to several catabolites, which are excreted mainly by the kidneys. Alteration of the pharmacokinetics of 5-FU and its catabolites as a result of renal dysfunction might augment systemic toxicity. Because no data are available for patients with severe renal failure, the pharmacokinetic parameters of 5-FU and its catabolites were determined for a patient with colorectal carcinoma and end-stage renal disease on maintenance hemodialysis therapy. Plasma was analyzed by 19F nuclear magnetic resonance spectroscopy for the first 5-day treatment cycle (daily bolus injections of 5-FU for 5 days in combination with low-dose folinic acid). On days 1 and 5, the pharmacokinetic parameters for 5-FU (total area under the plasma concentration-time curve, terminal half-life, total plasma clearance, volume of distribution based on the terminal phase) and its initial catabolite dihydrofluorouracil (total area under the plasma concentration-time curve, terminal half-life) were in the ranges reported in the literature for patients with normal renal function, implying no need for primary dose adjustment. In contrast, the final 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) accumulated to a concentration of 276 micromol/L on day 5 (approximately twofold higher than expected from the literature) despite good removal by hemodialysis with extraction ratios of 0.6 to 0.85 over the filter membrane. Negative effects of FBAL or enhancement of 5-FU-related toxicity could not be judged in this individual case, but further study is warranted to determine the possible benefits of more intensive dialysis treatment.
Rengelshausen
Jens
J
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. jens_rengelshausen@med.uni-heidelberg.de
Hull
William E
WE
Schwenger
Vedat
V
Göggelmann
Christoph
C
Walter-Sack
Ingeborg
I
Bommer
Jürgen
J
D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000601:surgery; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000628:therapy; D002955:Leucovorin / Q000008:administration & dosage; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis
D002955:Leucovorin; D005472:Fluorouracil