Application of 19F-n.m.r. spectroscopy to the identification of dog urinary metabolites of imirestat, a spirohydantoin aldose reductase inhibitor
| Autor: | P. J. Gilbert, C. W. Vose, T. E. Hartley, R. G. Turcan, J. A. Troke, K. V. Watson |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Health Toxicology and Mutagenesis Metabolite Glucuronidation Glucuronates Urine Toxicology Biochemistry Hydroxylation chemistry.chemical_compound Dogs Aldehyde Reductase medicine Animals Carbon Radioisotopes Chromatography High Pressure Liquid Pharmacology Aldose reductase Fluorenes biology Chemistry Hydantoins Hydrolysis General Medicine Fluorine Aldose reductase inhibitor Enzyme inhibitor biology.protein Glucuronide medicine.drug |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 22(7) |
| ISSN: | 0049-8254 |
| Popis: | 1. Urine from a dog dosed orally at 20 mg/kg with 14C-imirestat, a spirohydantoin aldose reductase inhibitor, contained 17.7 and 12.5% of the administered radioactivity at 0-48 and 48-72 h respectively. 2. Radio-h.p.l.c. of the 0-48 h urine revealed a complex mixture of metabolites and a small proportion of parent drug (1.6% of dose). Direct 19F-n.m.r. spectroscopy of this urine showed the fluoride ion, numerous metabolites which were predominantly glucuronide conjugates and, as a minor component, the parent drug. 3. After incubation with beta-glucuronidase the 0-48 h urine gave a 19F-n.m.r. spectrum showing fewer signals. This finding is consistent with aromatic ring hydroxylation followed by glucuronidation being the major metabolite pathways. 4. Deconjugated urine was analysed by proton-coupled 19F-n.m.r. and two-dimensional 19F-19F correlated spectroscopy. Results indicate that major components included three monohydroxy metabolites, a diphenol with both phenolic functions in the same ring, and a phenolic metabolite containing only one fluorine atom. 5. Semi-preparative h.p.l.c. of 0-48 h dog urine gave individual glucuronides isolated as mixtures of C-9 epimers. These fractions were hydrolysed and purified a second time by h.p.l.c. to give aglycones which were analysed by multi-nuclear n.m.r. and g.l.c.-mass spectrometry. The 3- and 4-hydroxy derivatives of imirestat were identified, as was the 2-hydroxy product obtained during or following defluorination. The other major aglycone was postulated to be the 3-fluoro-2-hydroxy metabolite. This represents a novel 'NIH-shift' type pathway for the metabolism of fluorobenzenes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|