Mechanism of metabolic cleavage of a furan ring
We studied the mechanism of metabolic cleavage of a furan ring, using a new hypolipidemic agent, ethyl 2-(4-chlorophenyl)-5-(2-furyl)oxazole-4-acetate (TA-1801), as a model compound. A TA-1801 analogue labeled with deuterium at the 5-position of its furan ring was administered orally to rats. The analysis of urinary metabolites by GC/MS revealed that the deuterium of the furan was retained in the ring-opened metabolite (M3). Metabolic cleavage of furan has been generally considered to proceed by hydroxylation of the 5-position followed by tautomerism and hydrolysis of the resulting 5-hydroxyfuran derivative. However, if the cleavage proceeded by this pathway, the deuterium of the 5-position would be eliminated during hydroxylation. Therefore, we propose that the ring was cleaved directly to form an unsaturated aldehyde, considering the mechanism of oxidation by cytochrome P-450. Although this intermediate was not detected in the biological specimens, a synthetic unsaturated aldehyde was transformed to the actual urinary metabolites M2 and M3 (major ring-opened metabolites) in the isolated rat liver.
- Research Organization:
- Tanabe Seiyaku Co., Ltd., Saitama (Japan)
- OSTI ID:
- 5164783
- Journal Information:
- Drug Metab. Dispos.; (United States), Journal Name: Drug Metab. Dispos.; (United States) Vol. 15:6; ISSN DMDSA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
BODY
CHEMICAL REACTIONS
CHROMATOGRAPHY
CLEAVAGE
CRYSTAL STRUCTURE
DEUTERIUM
DIGESTIVE SYSTEM
FURANS
GAS CHROMATOGRAPHY
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN ISOTOPES
HYDROXYLATION
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
LIVER
MAGNETIC RESONANCE
MAMMALS
MASS SPECTROSCOPY
METABOLISM
METABOLITES
MICROSTRUCTURE
NUCLEAR MAGNETIC RESONANCE
NUCLEI
ODD-ODD NUCLEI
ORAL ADMINISTRATION
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
RATS
REDOX REACTIONS
RESONANCE
RODENTS
SEPARATION PROCESSES
SPECTROSCOPY
STABLE ISOTOPES
TRACER TECHNIQUES
VERTEBRATES