Inhibition of drug metabolism by acute ethanol intoxication: A hepatic microsomal mechanism

Abstract

The effects of acute ethanol intoxication on drug metabolism were studied in man and rats. Ethanol ingestion significantly retarded the disappearance of pentobarbital and meprobamate from the blood in human volunteer subjects and rats. This was not due to altered compartmentalization, since total body disappearance of pentobarbital in rats was also delayed. In vitro, ethanol inhibited the metabolism of meprobamate by rat liver slices, which indicates a direct effect on hepatic drug metabolism. This effect was shown to involve inhibition of hepatic microsomal drug-metabolizing enzymes by ethanol, which was competitive or partially competitive. In addition ethanol decreased the activity of cytochrome P450 reductase, a rate limiting step in the electron transport chain of microsomal drug detoxification. The inhibition of drug metabolism demonstrated in this study may be due to the binding of ethanol to hepatic microsomes and its oxidation at this site.