Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine.
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.
Desmoulin
Franck
F
Groupe de Résonance Magnétique Nucléaire Biomédicale, Unité Mixte Recherche Centre National de la Recherche Scientifique 5623, Université Paul Sabatier, Toulouse, France. desmouli@chimie.ups-tise.fr
Gilard
Véronique
V
Malet-Martino
Myriam
M
Martino
Robert
R
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000652:urine; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil