Abstract
N-methyl Emetine, like the parent compound, emetine, has different effects on liver microsomal protein-synthesizing activity in the rat depending on whether experiments with this compound are performed in vivo or in vitro. Thus, the pretreatment of animals with N-methyl emetine in vivo at a dose level of 144 μmoles/kg stimulates the incorporation of labeled amino acid into protein in vitro by liver microsomal preparations from 24-hr pretreated rats. However, at the same dosage level, N-methyl emetine pretreatment for 2 hr inhibits the uptake of labeled amino acid into hepatic protein in vivo. In a third type of experiment, the addition of N-methyl emetine directly to a rat liver microsomal incubation system in vitro can completely inhibit the incorporation of l-( 14C)-phenylalanine into protein. These effects obtained with N-methyl emetine are less pronounced than corresponding effects observed with emetine. N-methyl Emetine is not ordinarily metabolized to emetine by N-demethylation in a rat liver microsomal drug-metabolizing system in vitro. However, liver microsomal preparations from phenobarbital-pretreated rats are capable of metabolizing N-methyl emetine by N-demethylation in vitro. Microsomal preparations from rats pretreated with N-methyl emetine at 144 μmole/ kg for 24 hr have a lower capacity for metabolizing drugs in vitro than do the controls. In corresponding experiments with the parent compound, greater inhibition of the drug-metabolizing enzymes in vitro occurs at a much lower pretreatment level with emetine. Substitution of emetine by alkylation of the secondary amine at position N-2′ therefore tends to diminish biological activity with respect to effects observable in liver microsomal preparations of the rat.
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