First-pass metabolism of ethanol is predominantly gastric

Oral consumption of alcohol results in much lower blood alcohol concentrations (BACs) than does the same dose administered intravenously, suggesting significant first-pass metabolism (FPM). The questions remain, however, (1) whether this difference truly represents FPM or simply reflects slower absorption of alcohol, and (2) if there is FPM, is it mainly of gastric or hepatic origin. To study this, rats were given the same dose alcohol (1 g/kg) by either intragastric intubation or by intravenous, intraportal, and intraduodenal infusions at a rate that mimicked the loss of alcohol from the stomach. Higher BAC levels after intravenous than intragastric alcohol indicated true FPM. Higher levels after intraportal or intraduodenal infusions (in fact, comparable to those obtained with the intravenous route) demonstrated negligible FPM when the route of delivery bypassed the stomach, yet included the liver. Furthermore, rats that had developed portosystemic shunts after ligation of the portal ven exhibited blood alcohol curves and FPM equivalent to those of sham-operated controls, indicating that FPM is not dependent on first-pass flow through the liver, but reflects gastric metabolism. The absence of significant hepatic FPM is attributable to the saturation of hepatic alcohol dehydrogenase by recirculating alcohol, resulting in no appreciable increase in metabolism secondary to newly absorbed alcohol. Finally, the in vivo gastric metabolism of alcohol in pylorus-ligated rats was demonstrated by significantly lower BACs when alcohol was administered intragastrically than when an amount identical to that lost from the ligated stomach was given intraportally. Thus, the lower BACs with oral as opposed to intravenous alcohol are not simply a consequence of slow absorption, but result from FPM occurring predominantly in the stomach.