The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

M Arellano,R Martino,M Malet-Martino,P Gires

doi:10.1038/bjc.1998.12

Abstract

We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-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(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) 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(-1) 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(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) 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, 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.

Highlights

Qualitative analysis isolated perfused rat liver (IPRL) were treated with pure FU at two doses, 45 mg kg-' body weight (n = 4) or a 'therapeutic' dose of 15 mg kg-' body weight (n = 5) for 3 h
The recording of 'H-coupled or -decoupled '9F-NMR spectra after addition of authentic f-hydroxypropionic acid (FHPA) and FAC to a concentrated perfusate from an IPRL experiment at 15 mg of FU kg-' body weight showed an increase in the signals located at -113.7 and -141.4 p.p.m., respectively, with the same coupling constants (Table 1)
Quantitative analysis We determined the amounts of unmetabolized FU, its different catabolites (FUPA, CFBAL, FBAL, F-) and the unknown compound at -110.1 p.p.m. from the values measured in the non-concentrated perfusates

Summary

Introduction

(except in the experiments at 15 mg kg-1 body weight), FBAL at -112.7 p.p.m., CFBAL at -1 11.5 p.p.m. and F- at -49.7 p.p.m. The differences in the values of 6 in non-concentrated and concentrated perfusates are mainly due to the much higher The recording of 'H-coupled or -decoupled '9F-NMR spectra after addition of authentic FHPA and FAC to a concentrated perfusate from an IPRL experiment at 15 mg of FU kg-' body weight showed an increase in the signals located at -113.7 and -141.4 p.p.m., respectively, with the same coupling constants (Table 1).

Results

Conclusion