Metabolic studies of tetrabenazine, a psychotropic drug in animals and man

Abstract

Following administration of tetrabenazine (2-oxo-3-isobutyl-9, 10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine) to animals or man, 9 metabolites of the drug were detected in the urine by thin layer chromatography. Five of these compounds were found unconjugated and 4 conjugated with glucuronic acid. The structures of all 5 unconjugated metabolites and of 2 aglucones Were established either by comparison in thin layer chromatography with synthetic compounds or by NMR mass spectroscopy and elemental analysis of metabolites isolated by column chromatography on silicic acid. The main steps of biological degradation of the drug are: reduction of the keto group at C 2 oxidation at position 2′ of the isobutyl side chain selective ether cleavage at C 9, followed by conjugation of the phenols to glucuronic acid. The same pattern of metabolite formation was observed in the rabbit, in the dog and in man. In all three species the glucuronides represent the prevailing form of excretion of the drug in the urine. A general scheme for the biological degradation of tetrabenazine is suggested. A description of the synthesis of several metabolites is given.