title: 5-fluorocytosine-related bone-marrow depression and conversion to fluorouracil: a pilot study.
abstract: The aim of this study is to investigate whether fluorouracil (5-FU) could be responsible for bone-marrow depression occurring in fluorocytosine (5-FC) treated patients. Six 5-FC treated patients were included in this pilot study. Toxicity was monitored by means of thrombocyte and leucocyte counts. 5-FC and 5-FU serum levels were measured using a high-performance liquid chromatography (HPLC) assay that allows simultaneous determination of both compounds. The amounts of 5-FU in the 34 available serum samples remained below the limit of quantitation (< 0.05 mg/L), whereas 5-FC levels could be detected in all samples. Instead, low levels of the 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) were detected in several of the investigated serum samples. In case of three patients thrombocyte counts remained within the normal range during 5-FC treatment, whereas one patient developed thrombocytopenia (50 x 10(9) thrombocytes/L) during therapy. Furthermore, one patient developed leucocytopenia (2.6 x 10(9) leucocytes/L) during 5-FC therapy, whereas the remaining five patients were suffering from leucocytosis prior to 5-FC therapy. In conclusion, we found nondetectable 5-FU serum concentrations (< 0.05 mg/L) in ICU patients treated with intravenous 5-FC, making it unlikely that 5-FC-associated toxicity results from 5-FU exposure in patients receiving intravenous 5-FC therapy. These findings may be explained by the fact that our patients received 5-FC intravenously instead of orally, therefore not allowing active conversion of 5-FC to 5-FU by the human intestinal microflora.
authors.affiliation: Department of Clinical Pharmacy, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: András
authors.initials: A
authors.lastname: Vermes
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Andre B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Jacob
authors.initials: J
authors.lastname: Dankert
mesh_terms: D000328:Adult; D000368:Aged; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D005472:Fluorouracil / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D007958:Leukocyte Count; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy; D008875:Middle Aged; D008962:Models, Theoretical; D010865:Pilot Projects; D010976:Platelet Count; D013921:Thrombocytopenia / Q000139:chemically induced; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine; D005437:Flucytosine; D005472:Fluorouracil