5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model.
We studied the effects of 5-ethynyluracil (GW776), a potent inactivator of dihydropyrimidine dehydrogenase, on the metabolism of 5-fluorouracil (5-FU), in particular with respect to formation of the toxic compounds fluoroacetate (FAC) and 2-fluoro-3-hydroxypropionic acid (FHPA), using fluorine-19 nuclear magnetic resonance and the isolated perfused rat liver model. Livers were perfused with 5-FU alone at a dose of 15 mg kg(-1) body weight or with 5-FU + GW776 at doses of 15 mg 5-FU kg(-1) body weight and 0.5 mg GW776 kg(-1) body weight injected 1 h before 5-FU. All 5-FU was metabolized in experiments with 5-FU alone whereas unmetabolized 5-FU represented 94% of the fluorinated compounds measured in experiments with 5-FU + GW776. GW776 modulated both the catabolic and the anabolic pathways of 5-FU, the most striking effect being on the degradative pathway. The amount of 5-FU catabolites decreased by a factor of 27 in the presence of GW776. The modulator led to a decrease in alpha-fluoro-beta-alanine (FBAL) formation by a factor of approximately 110, while fluoride ion formation decreased by a factor of approximately 10. By strongly lowering the metabolism of 5-FU into FBAL, GW776 circumvented the transformation of FBAL into toxic FAC and FHPA. 5-FU anabolites increased by a factor of approximately 7 in the presence of GW776. The level of free fluoronucleotides and 5-fluorouridine-5'-diphosphate sugars was increased up to fivefold. No incorporation of 5-FU into RNA could be measured in experiments with 5-FU alone whereas, although low (0.1% of 5-FU injected dose), it was detectable in experiments with 5-FU + GW776. These results suggest that GW776 may be useful for attenuating the not very common but serious cardiotoxic and/or neurotoxic side-effects of 5-FU that are probably due to FBAL metabolites.
Arellano
M
M
Biomedical NMR Group, IMRCP Laboratory, Université Paul Sabatier, Toulouse, France.
Malet-Martino
M
M
Martino
R
R
Spector
T
T
D000818:Animals; D001646:Bile / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005463:Fluoroacetates / Q000378:metabolism*; D005472:Fluorouracil / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
C109081:2-fluoro-3-hydroxypropionic acid; D004791:Enzyme Inhibitors; D005463:Fluoroacetates; C073482:eniluracil; D019344:Lactic Acid; D014498:Uracil; D005472:Fluorouracil