Disposition and first-pass metabolism of ethanol in humans: Is it gastric or hepatic and does it depend on gender?*

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Abstract
To assess the extent and site of the first-pass metabolism of ethanol and to examine whether first-pass metabolism and disposition of ethanol are dependent on gender. After a standardized lunch, healthy subjects (six women and six men) received on two separate occasions a 60-minute intravenous infusion of ethanol (0.3 gm/kg) and concomitantly an equimolar dose of d3-ethanol/kg either orally (over 20 minutes) or intraduodenally (infused over 30 minutes). Blood levels, urinary excretion of d0- and d3-ethanol, and sedative effects were monitored for 6 hours. Disposition and first-pass metabolism of ethanol were evaluated by applying an open two-compartment model with Michaelis-Menten elimination. Comparison of the corresponding intravenous/oral versus intravenous/intraduodenal data of each individual revealed that total first-pass metabolism (gastric plus hepatic) was not pronounced in either males (9.1% +/- 4.0%; mean +/- SD) or females (8.4% +/- 3.1%) and that this first-pass metabolism was partly of gastric origin. Dose-corrected values for area under blood concentration-time curve were on average 28% higher (p < 0.0001) in the women than in the men. Mean total blood ethanol disappearance rate was higher (p < 0.001) in women (3.92 +/- 0.40 mmol/L . hr) than in men (3.19 +/- 0.48 mmol/L . hr). Renal clearance was gender-independent and negligible. A linear relationship (p < 0.001) could be found between the blood levels of ethanol and sedation index. Because the slope was steeper in women (1.04) than in men (0.42) a higher central nervous system sensitivity to the sedative effects of ethanol in women can be assumed. Under realistic life conditions (social drinking of moderate doses of ethanol after a light lunch) only a minor, gender-independent first-pass metabolism is observed that is partly of gastric origin.