Selective Inhibition of Hepatic Microsomal Drug-Metabolism by Mexiletine Hydrochloride

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The inhibitory effects of mexiletine hydrochloride (MEX), an antiarrhythmic agent, on a monooxygenase system in mouse hepatic microsomes were studied. In vitro, MEX inhibited aniline hydroxylase and aminopyrine N-demethylase activities. The modes of inhibitions of these enzymes by MEX (mixed type) were similar to those cimetidine, while there was a great difference between inhibition constants (Ki) of MEX for aniline hydroxylase (0.05mM) and aminopyrine N-demethylase (1.26mM), in contrast to cimetidine which has a close similarity between K1 values of these enzymes. The effects of MEX on the stereospecific hydroxylations of testosterone were also measured MEX exhibited the inhibitory activities for 6β- and 7α- hydroxylations, while a little effect of MEX on 16α-hydroxylase activity was found. A spectrophotometric study revealed that MEX interacted directly with cytochrome P-450, but not with reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase. MEX inhibited competitively the binding of theophylline to cytochrome P-450 and its inhibitory potency was about 5-fold greater than that of cimetidine. These results indicated that MEX is a selective potent inhibitor of some cytochrome P-450-mediated drug-metabolism in hepatic microsomes.
日本医療薬学会の論文
1992-12-21