THE ANTICANCER DRUG 5-FLUOROURACIL IS METABOLIZED BY THE ISOLATED-PERFUSED RAT-LIVER AND IN RATS INTO HIGHLY TOXIC FLUOROACETATE

We report the first demonstration of the biotransformation of the anti -cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluor o-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAG), in the is olated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perf used with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body w eight, and rats were injected i.p. with 180 mg of FU kg(-1) body weigh t. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine show ed the presence of the normal metabolites of FU and low amounts of FHP A (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injecte d 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(-1) body weight, respecti vely; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 1 6.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body w eight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) wer e detected in perfusates, thus demonstrating that FHPA and FAC arise f rom FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FH PA is also cardiotoxic at high doses, the cardiotoxicity of FU might s tem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992, 1994), is the presence in commercial solu tions of FU of degradation products of FU that are metabolized into FH PA and FAG; these are formed over time in the basic medium necessary t o dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.