Summary We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, a-fluoro-f-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg-' body weight, and rats were injected i.p. with 180 mg of FU kg-' body weight.Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg-' body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg-' body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of a-fluoro-i-alanine (FBAL) hydrochloride at 16.6 mg kg-' body weight dose equivalent to 15 mg of FU kg-' body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992(Lemaire et al, , 1994, is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.Keywords: 5-fluorouracil; a-fluoro-J-alanine; '9F nuclear magnetic resonance; metabolism; fluoroacetate; a-fluoro-o-hydroxypropionic acid; isolated perfused rat liver; rat urine 5-Fluorouracil (FU) is widely used as an anti-tumour agent for treatment of solid tumours. Its chief side-effects are myelosuppression, diarrhoea, vomiting and mucositis. However, over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to FU has rapidly increased, probably because of the use of higher doses in continuous perfusion (Moertel et al, 1964;Rezkalla et al, 1989;Moore et al, 1990;Gamelin et al, 1991; De Fomi et al, 1992;Robben et al, 1993;Anand, 1994). The precise biochemical mechanism underlying these two side-effects remains unclear, although several investigators have postulated, but never demonstrated experimentally, that FU might be transformed into fluoroacetate (FAC), a highly cardiotoxic and neurotoxic poison (Koenig and Patel, 1970;Okeda et al, 1990). FAC enters the Krebs cycle and is then transformed into fluorocitrate, which inhibits the enzyme aconitase. Aconitase catalyses the conversion of citrate to isocitrate via the obligatory intermediate cis-aconitate. Inhibition of aconitase leads to a build-up of citrate in animal tissues (in particular heart) and serum, and the heart product...

Summary 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-' body weight or with 5-FU + GW776 at doses of 15 mg 5-FU kg-' body weight and 0.5 mg GW776 kg-' 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 a-fluoro-3-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.Keywords: 5-fluorouracil; 5-ethynyluracil (GW776); 19F nuclear magnetic resonance; modulation of 5-fluorouracil metabolism; fluoroacetate; 2-fluoro-3-hydroxypropionic acid; isolated perfused rat liver 5-Fluorouracil (5-FU) is one of the most commonly used anticancer agents for treatment of solid tumours. Common clinical adverse reactions include myelosuppression, diarrhoea, vomiting and mucositis. Over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to 5-FU has rapidly increased (Anand, 1994;Yeh and Cheng, 1994; and references cited therein). The biochemical mechanism underlying these toxic side-effects remains unclear, although it has been postulated that 5-FU, and more precisely its main catabolite ex-fluoro-p-alanine (FBAL) (Mukherjee and Heidelberger, 1960;Bemadou et al, 1985; Heggie et al, 1987; Hull et al, 1988), might be transformed into fluoroacetate (FAC) (Koenig and Patel, 1970), a highly cardiotoxic and neurotoxic poison (Pattison and Peters, 1966). We demonstrated on the isolated perfused rabbit heart model that commercial solutions of 5-FU contain cardiotoxic impurities, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), that are derived from...

An oral dose of 600 μg of misoprostol was found to be an acceptable and effective non-surgical option for treating incomplete abortion. Clinical trials.gov NCT00674232.