Studies of metabolic pathways of trimebutine by simultaneous administration of trimebutine and its deuterium-labeled metabolite

Journal Article · Sat Jul 01 00:00:00 EDT 1989 · Drug Metabolism and Disposition; (USA)

OSTI ID:5227524

Miura, Y; Chishima, S; Takeyama, S ^[1]

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1. 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), Vol. 17:4; ISSN 0090-9556
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
MALIC ACID
METABOLISM
BIOLOGICAL PATHWAYS
DEALKYLATION
DEUTERIUM
DOGS
ESTERASES
GAS CHROMATOGRAPHY
GENETIC VARIABILITY
GLUCURONIC ACID
HYDROLYSIS
IN VITRO
LIQUID COLUMN CHROMATOGRAPHY
LIVER
MASS SPECTROSCOPY
METABOLITES
MICROSOMES
ORAL ADMINISTRATION
RATS
REAGENTS
TRACER TECHNIQUES
ALDEHYDES
ANIMALS
BIOLOGICAL VARIABILITY
BODY
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHEMICAL REACTIONS
CHROMATOGRAPHY
DECOMPOSITION
DIGESTIVE SYSTEM
ENZYMES
GLANDS
HYDROGEN ISOTOPES
HYDROLASES
HYDROXY ACIDS
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
LYSIS
MAMMALS
NUCLEI
ODD-ODD NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANOIDS
ORGANS
RIBOSOMES
RODENTS
SEPARATION PROCESSES
SOLVOLYSIS
SPECTROSCOPY
STABLE ISOTOPES
VERTEBRATES
550501* - Metabolism- Tracer Techniques