First pass metabolism of ethanol: an important determinant of blood levels after alcohol consumption.

Alcohol consumption by rats fed ethanol-containing liquid diets is considerably greater than the measured rate of ethanol elimination from the blood, suggesting that a significant fraction of the alcohol ingested does not enter the systemic circulation. To assess the possibility of a first pass metabolism of ethanol, we compared the areas under the blood ethanol concentration curves after administration of various doses through various routes in alcohol-fed and control rats. In both groups, blood ethanol concentrations were significantly lower after intragastric than after intraportal or intravenous (femoral) administrations and, to a lesser extent, than after an intraduodenal dose. By contrast, the rise in blood acetate, a product of ethanol oxidation, was faster after intragastric administration. Moreover, absorption of the ethanol dose was virtually complete at the time of ethanol disappearance from the blood. The fraction of the dose that did not enter the systemic circulation was proportionally greater with the smaller doses. These results indicate that there is a significant first pass metabolism of ethanol which takes place in the gastrointestinal tract and particularly in the stomach, where alcohol dehydrogenase (ADH) activity is the highest. Chronic alcohol administration decreased ADH activity (probably secondary to gastric mucosal injury) and also decreased the magnitude of the first pass metabolism. The amount of ethanol ingested which does not enter the systemic circulation accounts for the apparent dissociation between alcohol consumption, blood ethanol levels and rate of blood ethanol elimination in alcohol-fed animals.