Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats

doi:10.1016/0002-9343(71)90270-1

The American Journal of Medicine

Volume 51, Issue 3, September 1971, Pages 346-351

https://doi.org/10.1016/0002-9343(71)90270-1 Get rights and content

Abstract

A previous study demonstrated that acute ethanol intoxication inhibits the rate of drug metabolism. To investigate the effects of chronic ethanol consumption on ethanol and drug metabolism, four alcoholic and four nonalcoholic volunteer subjects were given ethanol for one month under metabolic ward conditions. This resulted in accelerating the rate of disappearance of ethanol from the blood of the alcoholics and nonalcoholics from, respectively, 13.6 ± 2.4 and 13.8 ± 2.0 mg/100 ml/ hour during the control period to 18.5 ± 2.0 (P < 0.01) and 23.8 ± 2.0 (P < 0.05) after the ethanol period. In the same volunteer subjects, the rate of disappearance of meprobamate from the blood was also significantly accelerated from a mean half life of, respectively, 16.7 ± 2.5 and 13.7 ± 1.0 hours to 8.1 ± 1.5 (P < 0.02) and 8.2 ± 0.3 (P < 0.02). Urinary excretion of meprobamate was unaltered. Four to eight weeks after the end of the ethanol period the rate of disappearance of alcohol and meprobamate from the blood was restored to normal. The half life of pentobarbital was also measured in the four nonalcoholic subjects: there was a reduction from 35.1 ± 6.1 to 26.3 ± 6.3 hours after one month of ethanol feeding.

To study the mechanism of these effects, rat littermates were pair-fed adequate diets with 36 per cent of calories either as ethanol or carbohydrates; the half life of meprobamate was 254 ± 36 minutes in control animals versus 138 ± 19 minutes in rats fed ethanol for twenty-eight days (P < 0.02). Liver slices and 9,000 g microsomal preparations obtained from rats fed ethanol for one to three months showed significant increases in rates of meprobamate metabolism. Our study therefore demonstrates that chronic ethanol ingestion results in accelerated drug clearance from the blood caused, at least in part, by enhanced hepatic microsomal drug metabolism. This (in addition to central nervous system adaptation) helps to explain the tolerance to ethanol and other drugs which is known to develop in alcoholics.

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^☆: This study was presented in part at the Annual Meeting of American Association for the Study of Liver Diseases, Chicago, Illinois, October, 1969 [1], and supported by U.S. Public Health Service Grants MH 15558, AM 12511 and FR 71.

¹: From the Section of Liver Disease and Nutrition, Veterans Administration Hospital, Bronx, New York 10468 and the Departments of Medicine and Pathology, Mount Sinai School of Medicine of the City University of New York, New York, New York 10029.

^∗: Present address: 55, Allée des Rossignols, Montignies-le-Tilleul (H) 6110, Belgium.

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Clinical studyIncrease of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats☆

Abstract

Amer J Med

J Amer Pharm Ass

J Nutr

Amer J Clin Nutr

Anal Biochem

J Biol Chem

J Nutr

Amer J Clin Nutr

Metabolism

Biochem Pharmacol

Life Sci

Gastroenterology

Amer J Med

Life Sci

Amer J Clin Nutr

Effect of ethanol ingestion on ethanol, meprobamate and pentobarbital metabolism (abstract)

Gastroenterolpgy

An experimental study of the etiology of “rum fits” and delirium tremens

Quart J Stud Alcohol

Wechselwirkungen zwischen Alkohol und Arzneimitteln

Deutsch Med Wschr

Combined Effects of Alcohol and Other Drugs

Ethanol oxidation by hepatic microsomes: adaptive increase after ethanol feeding

Science

Clinical study
Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats☆