1. The metabolic pathway(s) of
OGT 719, a novel
nucleoside analogue in which
galactose is covalently attached to the N1 of
5-fluorouracil (FU), have been investigated with (19)F-NMR spectroscopy in (1) the isolated perfused rat liver (IPRL) model, (2) normal rats, (3) rats bearing the HSN LV10
sarcoma, (4) nude mice xenografted with the human
hepatoma HepG2 and (5) urine from patients. 2. The administration of
OGT 719 results in the formation of small amounts of FU. IPRL experiments with
OGT 719 in combination with
asialofetuin, a natural
asialoglycoprotein receptor (
ASGP-r), suggest competitive binding of
OGT 719 to the
ASGP-r. 3. The data obtained in non-tumour rats also demonstrated an extremely low metabolization of
OGT 719 into FU and
alpha-fluoro-beta-alanine, the well-known major metabolite of FU. 4. A comparison of tumour extracts from rats bearing the HSN LV10
sarcoma treated with FU or
OGT 719 showed the incorporation of FU into
RNA in rats treated with FU but not in rats treated with
OGT 719; nevertheless, the incorporation of FU into
RNA was observed in the liver from rats treated with
OGT 719. 5. In a human
hepatoma xenografted to nude mice, both the
OGT 719 and FU contents of the tumour were markedly higher than in the corresponding liver, suggesting a tumour-specific trapping of
OGT 719 in
hepatoma. 6. The metabolism of
OGT 719 was also extremely low in patients. 7. In conclusion, the present study shows the value of (19)F-NMR for demonstrating for the first time that
OGT 719 is a
prodrug of FU although very poorly metabolized.