Studies of metabolic pathways of trimebutine by simultaneous administration of trimebutine and its deuterium-labeled metabolite
- Tanabe Seiyaku Co., Ltd., Saitama (Japan)
Trimebutine maleate (I), (+-)-2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate hydrogen maleate, and a deuterium-labeled sample of its hydrolyzed metabolite, 2-dimethylamino-2-phenylbutanol-d3 (II-d3), were simultaneously administered to experimental animals at an oral dose of 10 or 50 mumol/kg, and distribution ratios of the two alternative initial metabolic steps, i.e., ester hydrolysis and N-demethylation, were estimated by determining the composition of the urinary alcohol-moiety metabolites, II, and its mono- and di-demethylated metabolites, III and IV, by GC/MS. In dogs, the order of quantities of the metabolites from II-d3 was II much greater than III much greater than IV, showing predominance of conjugation over N-demethylation. However, this order was reversed when the amounts of the metabolites from I were compared, indicating that I was preferentially metabolized by N-demethylation followed by ester hydrolysis and conjugation in this order. In rats, a considerable proportion of I was presumed to be metabolized by ester hydrolysis before N-demethylation. In in vitro experiments employing the liver microsomes and homogenates of liver and small intestine from rats and dogs, it was found that both ester-hydrolizing and N-demethylating activities were higher in rats than in dogs, and the conjugating activity was higher in dogs than in rats. It was also found that I, having a high lipophilicity, was more susceptible to N-demethylation than less lipophilic II. These results from the in vitro experiments could account for the species differences in the distribution ratio of the metabolic pathways of I in vivo.
- OSTI ID:
- 5227524
- Journal Information:
- Drug Metabolism and Disposition; (USA), Journal Name: Drug Metabolism and Disposition; (USA) Vol. 17:4; ISSN DMDSA; ISSN 0090-9556
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ALDEHYDES
ANIMALS
BIOLOGICAL PATHWAYS
BIOLOGICAL VARIABILITY
BODY
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHEMICAL REACTIONS
CHROMATOGRAPHY
DEALKYLATION
DECOMPOSITION
DEUTERIUM
DIGESTIVE SYSTEM
DOGS
ENZYMES
ESTERASES
GAS CHROMATOGRAPHY
GENETIC VARIABILITY
GLANDS
GLUCURONIC ACID
HYDROGEN ISOTOPES
HYDROLASES
HYDROLYSIS
HYDROXY ACIDS
IN VITRO
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
LIQUID COLUMN CHROMATOGRAPHY
LIVER
LYSIS
MALIC ACID
MAMMALS
MASS SPECTROSCOPY
METABOLISM
METABOLITES
MICROSOMES
NUCLEI
ODD-ODD NUCLEI
ORAL ADMINISTRATION
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANOIDS
ORGANS
RATS
REAGENTS
RIBOSOMES
RODENTS
SEPARATION PROCESSES
SOLVOLYSIS
SPECTROSCOPY
STABLE ISOTOPES
TRACER TECHNIQUES
VERTEBRATES