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.

To determine whether the first-pass metabolism (FPM) of orally consumed alcohol varies with the time of day, 12 healthy male subjects were tested with both oral and intravenous alcohol (0.3 g/kg), in the morning and evening, always 1 hr after the same standard meal. The results revealed no significant differences in FPM (81.6 +/- 11.6 vs 92.8 +/- 10.6 mg/kg) or in any other index of alcohol absorption and metabolism. Eleven subjects were also tested in the evening after treatment with cimetidine, an H2-antagonist that inhibits gastric alcohol dehydrogenase activity in vitro. Compared to baseline, cimetidine (1 g/day for eight days) significantly decreased FPM (from 100.1 +/- 8.0 to 52.6 +/- 11.4 mg/kg, P < 0.01) and increased the systemic bioavailability of alcohol (from 66 +/- 3 to 82 +/- 4%, P < 0.01), as well as peak blood alcohol concentrations (from 4.3 +/- 0.4 to 5.9 +/- 0.5 mM, P < 0.05) and areas under the curve (from 5.1 +/- 0.5 to 7.0 +/- 0.5 mM/hr, P < 0.01). The results indicate the absence of diurnal variation in FPM and suggest that patients given cimetidine should be warned of its possible interaction with alcohol regardless of the time of day.