Capecitabine (
Xeloda; CAP) is a recently developed oral
antineoplastic prodrug of
5-fluorouracil (5-FU) with enhanced
tumor selectivity. Previous studies have shown that CAP activation follows a pathway with three enzymatic steps and two intermediary metabolites,
5'-deoxy-5-fluorocytidine (5'-DFCR) and
5'-deoxy-5-fluorouridine (5'-DFUR), to form
5-FU preferentially in
tumor tissues. In the present work, we investigated all fluorinated compounds present in liver, bile, and perfusate medium of isolated perfused rat liver (IPRL) and in liver, plasma, kidneys, bile, and urine of healthy rats. Moreover, data obtained from rat urine were compared with those from mice and human urine. According to a low
cytidine deaminase (3.5.4.5) activity in rats,
5'-DFCR was by far the main product in perfusate medium from IPRL and plasma and urine from rats. Liver and circulating
5'-DFCR in perfusate and plasma equilibrated at the same concentration value in the range 25 to 400 microM, which supports the involvement of es-type
nucleoside transporter in the liver.
5'-DFUR and
alpha-fluoro-beta-ureidopropionic acid (
FUPA) +
alpha-fluoro-beta-alanine (
FBAL) were the main products in urine of mice, making up 23 to 30% of the administered dose versus 3 to 4% in rat. In human urine,
FUPA +
FBAL represented 50% of the administered dose,
5'-DFCR 10%, and
5'-DFUR 7%. Since
fluorine-19 nuclear magnetic resonance spectroscopy gives an overview of all the fluorinated compounds present in a sample, we observed the following unreported metabolites of CAP: 1) 5-fluorocytosine and its hydroxylated metabolite, 5-fluoro-6-hydroxycytosine, 2)
fluoride ion, 3) 2-fluoro-3-hydroxypropionic
acid and fluoroacetate, and 4) a glucuroconjugate of 5'-DFCR.