HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Metabolism of a novel nucleoside analogue, OGT 719, in the isolated perfused rat liver model, in rats, in tumour models and in patients.

Abstract
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.
AuthorsF Desmoulin, V Gilard, M Malet-Martino, R Martino, C Molina, P Smith
JournalXenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 33 Issue 3 Pg. 289-303 (Mar 2003) ISSN: 0049-8254 [Print] England
PMID12637246 (Publication Type: Clinical Trial, Journal Article)
Chemical References
  • Asialoglycoproteins
  • Fetuins
  • Fluorine Radioisotopes
  • OGT 719
  • alpha-Fetoproteins
  • asialofetuin
  • Glucuronidase
  • Fluorouracil
Topics
  • Animals
  • Asialoglycoproteins (pharmacology)
  • Biotransformation
  • Fetuins
  • Fluorine Radioisotopes
  • Fluorouracil (analogs & derivatives, metabolism, pharmacokinetics, urine)
  • Glucuronidase (chemistry)
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Liver (metabolism)
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Nude
  • Neoplasms (metabolism)
  • Neoplasms, Experimental (metabolism)
  • Rats
  • Rats, Wistar
  • Sarcoma, Experimental (metabolism)
  • Transplantation, Heterologous
  • alpha-Fetoproteins (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: