Studies of metabolic pathways of trimebutine by simultaneous administration of trimebutine and its deuterium-labeled metabolite.
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.
Miura
Y
Y
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Chishima
S
S
Takeyama
S
S
D000818:Animals; D001565:Benzoates / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D003903:Deuterium; D004285:Dogs; D004950:Esterases / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005965:Glucuronates / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012997:Solvents; D014287:Trimebutine / Q000378:metabolism*
D001565:Benzoates; D005965:Glucuronates; D007202:Indicators and Reagents; D012997:Solvents; D003903:Deuterium; D004950:Esterases; D014287:Trimebutine