Direct detection of new flucytosine metabolites in human biofluids by 19F nuclear magnetic resonance
Vialaneix, J.P.; Malet-Martino, M.C.; Hoffmann, J.S.; Pris, J.; Martino, R.
Drug Metabolism and Disposition the Biological Fate of Chemicals 15(5): 718-724
1987
ISSN/ISBN: 0090-9556 PMID: 2891491 Document Number: 297364
19F nuclear magnetic resonance was used for the analysis of 5-fluorocytosine (FC) metabolites in biological fluids of a patient with cryptococcal meningitis who was intravenously injected with this drug at a daily dose of 7.5 g (2.5 g at 8-h intervals). This method allows a direct, simultaneous, and quantitative determination of all the fluorinated metabolites of FC, in the range of sensitivity allowed by the spectrometer (sensitivity threshold, 0.01 mM). In urine, in addition to previously reported metabolites (unmetabolized FC and alpha -fluoro- beta -alanine (FBAL)), 3 new metabolites were identified: a glucuronide of FC (GLFC), 6-hydroxy-5-fluorocytosine (6OHFC), and fluoride ion F-. The same metabolites (except F-) were found in plasma. In cerebrospinal fluid, only unchanged FC and GLFC were observed. The total urinary excretion during an 8-h period between 2 injections of FC was 100.4% of the injected dose. Unchanged FC was the major excretory product accounting for 96.1% of the total. GLFC and 6OHFC made up, respectively, 2.7% and 1.2% of the excreted metabolites. The proportions of F- and FBAL were very low, respectively, 0.3% and 0.1% of the excreted metabolites. The global urinary excretion over a 24-h period was 102% of the injected dose. The proportions of metabolites were very close to those obtained for the 8-h period. In plasma, the proportions of metabolites were analogous to those determined in urine. In cerebrospinal fluid, GLFC represents 1% of the fluorinated metabolites. It is concluded that there is a minor pathway of FC deamination in humans and 2 other pathways of FC catabolism, one involving FC hydroxylation, the other its glucuroconjugation, are suggested.