[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].
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.
Kuwata
K
K
Pharmacokinetics Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd.
Nagayama
S
S
Hirakawa
Y
Y
Matsushima
E
E
Kawaguchi
Y
Y
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D005467:Floxuridine / Q000008:administration & dosage*; D005472:Fluorouracil / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D005641:Tegafur / Q000008:administration & dosage*; D014498:Uracil / Q000008:administration & dosage; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000097:blood
D005467:Floxuridine; D015091:beta-Alanine; D005641:Tegafur; C032348:alpha-fluoro-beta-alanine; D014498:Uracil; D005472:Fluorouracil; C025034:doxifluridine