Abstract
Geissoschizine methyl ether (GM) is an indole alkaloid found in Uncaria hook, which is a galenical constituent of yokukansan, a traditional Japanese medicine. GM has been identified as the active component responsible for anti-aggressive effects. In this study, the metabolic profiling of GM in rat and human liver microsomes was investigated. Thirteen metabolites of GM were elucidated and identified using a high-performance liquid chromatography with tandem mass spectrometry method, and their molecular structures were proposed on the basis of the characteristics of their precursor ions, product ions, and chromatographic retention times. There were no differences in the metabolites between the rat and human liver microsomes. Among the 13 identified metabolites, there were two demethylation metabolites, one dehydrogenation metabolite, three methylation metabolites, three oxidation metabolites, two water-adduct metabolites, one di-demethylation metabolite, and one water-adduct metabolite followed by oxidation. The metabolic pathways of GM were proposed on the basis of this study. This study will be helpful in understanding the metabolic routes of GM and related Uncaria hook alkaloids, and provide useful information on the pharmacokinetics and pharmacodynamics. This is the first report that describes the separation and identification of GM metabolites in rat and human liver microsomes.
Highlights
Geissoschizine methyl ether [(16E,19E)-16,17,19,20-tetradehydro-17-methoxycorynan-16-carboxylic acid methyl ester, GM, Figure 1] is a major indole alkaloid found in Uncaria hook, which is a galenical constituent of yokukansan, a traditional Japanese medicine (Kampo)
There were no differences in the metabolites produced between the rat and human liver microsomes
These results suggest that GM was metabolized to two demethylation metabolites in rat and human liver microsomes
Summary
Geissoschizine methyl ether [(16E,19E)-16,17,19,20-tetradehydro-17-methoxycorynan-16-carboxylic acid methyl ester, GM, Figure 1] is a major indole alkaloid found in Uncaria hook, which is a galenical constituent of yokukansan, a traditional Japanese medicine (Kampo). Rhynchophylline, hirsutine, hirsuteine, and GM were detected; only GM was detected in the brain These results suggest that GM is an active component contributing to the pharmacological effect of yokukansan. The metabolic fate of hirsutine and hirsuteine, indole alkaloids with chemical structures similar to that of GM, was investigated in rats [8]. The metabolism of yokukansan in rat urine was investigated, and 18-hydroxy GM was identified as the metabolite of GM [11]. To examine the activity of yokukansan, the metabolic fate of GM must be investigated. In this study, to evaluate the metabolic profile of GM, the metabolites of GM obtained from rat and human liver microsomes were investigated using LC/MS/MS, and the MS2 spectra were used to determine their composition and structure
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