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 inactivato r of dihydropyrimidine dehydrogenase, on the metabolism of 5-fluoroura cil (5-FU), in particular with respect to formation of the toxic compo unds fluoroacetate (FAG) 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 befor e 5-FU. All 5-FU was metabolized in experiments with 5-FU alone wherea s unmetabolized 5-FU represented 94% of the fluorinated compounds meas ured in experiments with 5-FU + GW776. GW776 modulated both the catabo lic and the anabolic pathways of 5-FU, the most striking effect being on the degradative pathway. The amount of 5-FU catabolites decreased b y a factor of 27 in the presence of GW776. The modulator led to a decr ease in a-fluoro-P-alanine (FBAL) formation by a factor of approximate ly 110, while fluoride ion formation decreased by a factor of approxim ately 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 o f GW776. The level of free fluoronucleotides and 5-fluorouridine-5'-di phosphate sugars was increased up to fivefold. No incorporation of 5-F U into RNA could be measured in experiments with 5-FU alone whereas, a lthough low (0.1% of 5-FU injected dose), it was detectable in experim ents with 5-FU + GW776. These results suggest that GW776 may be useful for attenuating the not very common but serious cardiotoxic and/or ne urotoxic side-effects of 5-FU that are probably due to FBAL metabolite s.