Gender differences in pharmacokinetics of alcohol

Background: The enhanced vulnerability of women to develop alcohol-related diseases may be due to their higher blood alcohol levels after drinking, bu t the mechanism for this effect is debated. Methods: Sixty-ftve healthy volunteers of both genders drank 0.3 g of ethan ol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood a lcohol concentrations were monitored by breath analysis and compared with t hose after intravenous infusion of the same dose. First-pass metabolism was quantified (using Michaelis-Menten kinetics) as the route-dependent differ ence in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 mu Curie of technetiu m-labeled diethylene triamine pentacetic acid in 10% ethanol. The activitie s of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, u sing preferred substrates for gamma -ADH (acetaldehyde) and for sigma -ADH (m-nitrobenzaldehyde) and a specific reaction of chi -ADH (glutathione-depe ndent formaldehyde dehydrogenase). Results: Women had less first-pass metabolism than men when given 10% or 40 %, but not 5%, alcohol. This was associated with lower gastric chi -ADH act ivity; its low affinity for ethanol could explain the greater gender differ ence in first-pass metabolism with high rather than with low concentrations of imbibed alcohol, Alcohol gastric emptying was 42% slower and hepatic ox idation was 10% higher in women. A 7.3% smaller volume of alcohol distribut ion contributed to the higher ethanol levels in women, but it did not accou nt for the route-dependent effects. Conclusions: The gender difference in alcohol levels is due mainly to a sma ller gastric metabolism in females (because of a significantly lesser activ ity of chi -ADH), rather than to differences in gastric emptying or in hepa tic oxidation of ethanol. The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences ma y increase the vulnerability of women to the effects of ethanol.