DIRECT DETECTION OF NEW FLUCYTOSINE METABOLITES IN HUMAN BIOFLUIDS BY F-19 NUCLEAR-MAGNETIC-RESONANCE

  • 1 September 1987
    • journal article
    • research article
    • Vol. 15  (5) , 718-724
Abstract
19F nuclear magnetic resonance was used for the analysis of flucytosine (FC; 5-fluorocytosine) 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-hr 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 the already reported metabolites [unmetabolized FC and .alpha.-fluoro-.beta.-alanine (FBAL)], three 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-hr period between two injections of FC was 100.4% of the injected dose. Unchanged FC was the major secretory 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-hr period was 102% of the injected dose. The proportions of metabolites were very close to those obtained for the 8-hr period. In plasma, the proportions of metabolites were analogous to those determined in urine. In cerebrospinal fluid, GLFC represents 1% of the fluorinated metabolites. Our study confirms the minor pathway of FC deamination in humans already reported by other authors and suggests two other pathways of FC catabolism, one involving FC hydroxylation, the other its glucuroconjugation.