Factors involved in the inhibition of drug metabolism by (—)-emetine

Abstract

The oxidative N-demethylation of aminopyrine and of N-ethyl morphine as well as the S-demethylation of 6-methylmercaptopurine riboside in vitro is inhibited by about 50 per cent in liver microsomal preparations from rats pretreated for 24 hr with (—)-emetine dihydrochloride (18 μmoles/kg). Under these conditions, the azo-reduction of neoprontosil is also inhibited, although NADPH-cytochrome c reductase and neotretrazolium diaphorase activities are unaffected. The inhibition of drug-metabolizing enzyme activities in vitro appears to be related to a lowering of the liver microsomal cytochrome P-450 and cytochrome b 5 content. When emetine is added directly to control liver microsomal incubations for the assay of N- or S-demethylation of substrates as above, and aromatic ring hydroxylation of aniline in vitro, drug-metabolizing enzyme activities are also inhibited under those circumstances. Emetine appears to be a competitive inhibitor of the N-demethylation of aminopyrine. The interaction of emetine and liver microsomal cytochrome P-450 is associated with spectral changes more closely resembling those of aniline (type II) than those of 6-methylmercaptopurine riboside (type I).