Metabolism of Ipecac Alkaloids Cephaeline and Emetine by Human Hepatic Microsomal Cytochrome P450s, and Their Inhibitory Effects on P450 Enzyme Activities

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In this study, we identfied the metabolites and the CYP forms that are specifically involved in emetine Odemethylation in human liver microsomes, and cleared the inhibitory potential of caohaeline and emetime on the activity of the major drug-metabolizing CYP enzymes. Incubation of emetine with human liver microsomes yielded three metabolited identified by using HPLC by comparison of the retention time with the authertic sample of cephaeline, 9-O-demonthylemetine and CYP3A4 also participared in metabolism. IC_<50> for cephaeline against CYP2D6 and CYP3A4 were 121 and 1000μ_M, respectively. Inhibition constants (K_i)for both compounds on the CYP2D6 and CYP3A4 activities were determined by graphic analysis of Dixon plots at vattious concentratrions. The obtains K_i values of ceohaeline for CYP2D6 and CYP3A4 were 54 and 355μ_M, respectively, and the values of emetine were 43 and 232μ_M, respectively. We concluded that these in vitro inhivitions of cephaeline and emetime would handly increase plasma concentrations of co-administered drugs in clinical therapy.
公益社団法人日本薬学会の論文
2001-06-01