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), Vol. 15:6
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
FURANS
CLEAVAGE
METABOLISM
DEUTERIUM
GAS CHROMATOGRAPHY
HYDROXYLATION
LIVER
MASS SPECTROSCOPY
METABOLITES
NUCLEAR MAGNETIC RESONANCE
ORAL ADMINISTRATION
RATS
REDOX REACTIONS
TRACER TECHNIQUES
ANIMALS
BODY
CHEMICAL REACTIONS
CHROMATOGRAPHY
CRYSTAL STRUCTURE
DIGESTIVE SYSTEM
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
MAGNETIC RESONANCE
MAMMALS
MICROSTRUCTURE
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
RESONANCE
RODENTS
SEPARATION PROCESSES
SPECTROSCOPY
STABLE ISOTOPES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550501 - Metabolism- Tracer Techniques