[Comparison of pharmacokinetics of 5-FU and alpha-fluoro-beta-alanine, a metabolite of 5-FU, in plasma after administration of UFT, tegafur, 5-FU or doxifluridine to rats]

Abstract

Toxic effects (neurotoxicity and cardiotoxicity) of 5-FU and its derivatives have been reported by many investigators. These toxicities are considered to be caused by the inhibition of the TCA cycle by alpha-fluoro-beta-alanine (FBAL), a metabolite of 5-FU, and later metabolites. In this study, we focused on FBAL as an index of the above toxicities. We compared the concentrations of 5-FU and FBAL in plasma after administration of UFT, tegafur (FT), 5-FU or doxifluridine (5'-DFUR) to rats (75 mumol/kg) in order to evaluate which compound has the better balance of efficacy and toxicity. UFT exhibited the lowest FBAL concentration in plasma followed by FT, 5'-DFUR and 5-FU. The ratio of FBAL to 5-FU in Cmax and AUC after dosing of UFT was the lowest among these four test compounds. These data indicate that the lowest ratio of FBAL to 5-FU resulted from the inhibitory effect of uracil, a component of UFT, on the metabolism of 5-FU. In conclusion, the present results suggest that UFT has a better balance of efficacy and toxicity than FT, 5-FU and 5'-DFUR.