Effects of ranitidine on blood alcohol levels after ethanol ingestion. Comparison with other H2-receptor antagonists.

OBJECTIVE: To determine whether the H2-receptor antagonist, ranitidine, which is a potent inhibitor of gastric alcohol dehydrogenase activity in vitro, increases the bioavailability of orally administered ethanol (0.3 g/kg of body weight) and to compare the resulting blood alcohol concentrations with those of two other H2-antagonists, cimetidine and famotidine, the latter of which does not inhibit gastric alcohol dehydrogenase. DESIGN: For each of the H2-receptor antagonists, a different group of subjects was used. In each group, a paired design was adopted with each subject serving as his own control. SETTING: Hospital laboratory. SUBJECTS: Normal, healthy men aged 24 to 46 years. INTERVENTION: Eight men were treated for 1 week with ranitidine (300 mg/d), six with cimetidine (1000 mg/d), and six with famotidine (40 mg/d). MEASURES: Peak blood alcohol concentrations, areas under the blood alcohol curve, first-pass metabolism, and bioavailability of orally consumed ethanol. RESULTS: Relative to baseline, ranitidine increased the mean peak concentration and the area under the curve of blood alcohol concentrations by 34% (P less than .05) and 41% (P less than .01), respectively. First-pass metabolism of ethanol was decreased from 70 +/- 10 to 31 +/- 9 mg/kg of body weight, with a corresponding increase in ethanol bioavailability of 79.6% to 92.6%. By comparison, cimetidine had even a greater effect on blood alcohol levels, while famotidine had no significant effects. CONCLUSION: Patients treated with ranitidine or cimetidine should be warned of possible functional impairments after consumption of amounts of ethanol considered safe in the absence of such therapy.

Gastric origin of the first-pass metabolism of ethanol in humans: effect of gastrectomy.

The areas under the curve (AUCs) of blood ethanol concentrations are much smaller after oral than after intravenous administration of a small dose of ethanol. To study whether this difference is due to ethanol oxidation in the stomach, in the small intestine, or during first pass through the liver, we compared the AUCs after random administration of the same ethanol dose by the intravenous, oral, and intraduodenal routes to 5 abstaining alcoholics and via the two former routes to 10 subjects with Billroth II subtotal gastrectomy. In the nonoperated subjects, the AUCs after an ethanol dose (0.15 g/kg) given orally were 17% (p less than 0.01) of those achieved intravenously, in spite of the fact that greater than 99% of the dose had disappeared from the stomach at the completion of the AUC. By contrast, the AUCs after intraduodenal administration did not differ from those produced intravenously, indicating that neither the intestine nor the liver make a detectable contribution to this first-pass metabolism. Moreover, gastrectomy completely abolished the first-pass metabolism of ethanol. Gastric metabolism decreases the bioavailability of the ingested alcohol and thus attenuates its systemic toxicity. The abolition of this "protective barrier" in gastrectomized patients may increase their vulnerability to ethanol.

Effects of fasting and chronic alcohol consumption on the first-pass metabolism of ethanol.

The present investigation was undertaken to evaluate what fraction of alcohol ingested in amounts during usual "social drinking" does not enter the systemic circulation. To that effect, on consecutive days, either peroral or intravenous ethanol was administered in both fed and fasted states to 7 nonalcoholic and 18 alcoholic subjects. In nonalcoholics consuming 0.15 g/kg body wt ethanol, the magnitude of first-pass metabolism of ethanol was 3.94 +/- 0.15 mmol/L X h, calculated as the difference of the areas under the curve obtained after oral and intravenous alcohol administration. The first-pass metabolism accounted for 73% of the latter. When the administered dose was increased to 0.3 g/kg body wt ethanol, the corresponding values were 6.46 +/- 0.50 mmol/L X h and 44%. Fasting decreased this effect. When alcoholics consumed 0.15 g/kg body wt ethanol, the corresponding values were 0.92 +/- 0.65 mmol/L X h and 23%. When these alcoholics were fasted, the first-pass metabolism again decreased and it was significantly lower than in the nonalcoholics tested under the same conditions. We conclude that in humans a significant fraction of ingested alcohol undergoes first-pass metabolism but that this effect is reduced in alcoholics and by fasting. The magnitude of this process determines the bioavailability of alcohol and thus modulates its potential toxicity.

Transport of acetaldehyde in red blood cells.

Alcohol intake caused a much greater elevation of acetaldehyde in red blood cells than in plasma. During ethanol oxidation, most of this metabolite was released from the splanchnic areas and circulated reversibly bound to intracellular components of the erythrocyte. Acetaldehyde was then taken up by extra-splanchnic tissues from both plasma and erythrocytes. Thus, an amount of acetaldehyde much larger than previously thought by measurements in plasma becomes available to exert extra-splanchnic toxicity. The contribution of this route for acetaldehyde transport is markedly enhanced in alcoholics.