EVIDENCE FOR THE IMPORTANCE OF 5'-DEOXY-5-FLUOROURIDINE CATABOLISM IN HUMANS FROM F-19 NUCLEAR-MAGNETIC-RESONANCE SPECTROMETRY

  • 1 April 1986
    • journal article
    • research article
    • Vol. 46  (4) , 2105-2112
Abstract
The use of a new methodology, 19F nuclear magnetic resonance, has allowed detection of all the fluorinated metabolites in the biofluids of patients treated with 5''-deoxy-5-fluorouridine (5''-dFUrd) injected i.v. at a dose of 10 g/m2 over 6 h. This technique, which requires no labeled drug, allows a direct study of the biological sample with no need for extraction or derivatization and a simultaneous identification and quantitation of all the different fluorinated metabolites. As well as the already known metabolites, unmetabolized 5''-dFUrd, 5-fluorouracil, and 5,6-dihydro-5-fluorouracil, the presence of .alpha.-fluoro-.beta.-ureidopropionic acid, .alpha.-fluoro-.beta.-alanine (FBAL), N-carboxy-.alpha.-fluoro-.beta.-alanine, and the fluoride anion F- is reported. The catabolic pathway proposed for 5''-dFUrd is analogous to that of 5-fluorouracil, completed with FBAL .fwdarw. F- step, and the plasmatic equilibrium of FBAL with N-carboxy-.alpha.-fluoro-.beta.-alanine, its N-carboxy derivative. The quantitative analysis of the different metabolites found in plasma and urine emphasizes the significance of the catabolic pathway. High concentrations of .alpha.-fluoro-.beta.-ureidopropionic acid and FBAL are recovered in plasma from 3 h after the beginning of the perfusion to 1 h after its end. The global urinary excretion results show that there is a high excretion of 5''-dFUrd and metabolites. Unchanged 5''-dFUrd and FBAL are by far the major excretory products and are at nearly equal rates. The protocol followed in this study produces relatively low but persistent plasmatic concentrations of 5-fluorouracil throughout the perfusion.