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, but the mechanism for this effect is debated. METHODS: Sixty-five healthy volunteers of both genders drank 0.3 g of ethanol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood alcohol concentrations were monitored by breath analysis and compared with those after intravenous infusion of the same dose. First-pass metabolism was quantified (using Michaelis-Menten kinetics) as the route-dependent difference in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 microCurie of technetium-labeled diethylene triamine pentacetic acid in 10% ethanol. The activities of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, using preferred substrates for gamma-ADH (acetaldehyde) and for final sigma-ADH (m-nitrobenzaldehyde) and a specific reaction of chi-ADH (glutathione-dependent 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 activity; its low affinity for ethanol could explain the greater gender difference in first-pass metabolism with high rather than with low concentrations of imbibed alcohol. Alcohol gastric emptying was 42% slower and hepatic oxidation was 10% higher in women. A 7.3% smaller volume of alcohol distribution contributed to the higher ethanol levels in women, but it did not account for the route-dependent effects. CONCLUSIONS: The gender difference in alcohol levels is due mainly to a smaller gastric metabolism in females (because of a significantly lesser activity of chi-ADH), rather than to differences in gastric emptying or in hepatic oxidation of ethanol. The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol.

Contribution of gastric oxidation to ethanol first-pass metabolism in baboons.

BACKGROUND: A portion of ingested alcohol does not reach the systemic blood, undergoing a first-pass metabolism (FPM) during gastric and hepatic circulation. METHODS: To determine whether the stomach can metabolize sufficient ethanol to account for the FPM, and to what extent gastric alcohol dehydrogenase (ADH) activity is responsible, the hepatic vein, the portal vein, and the aorta were cannulated nonocclusively in baboons to measure the conversion of ethanol to acetate in vivo. 14C-ethanol (300 mg/kg as a 15% solution) was given intragastrically (IG) whereas 3H-acetate was continuously infused intravenously (IV). 14C-acetate was measured after exhaustive evaporation of ethanol. Simultaneous sampling of hepatic venous, portal and arterial blood was carried out for 3 hr, at the end of which the same alcohol dose was given IV to calculate the Michaelis-Menten parameters of elimination. RESULTS: Analysis of the IV and IG ethanol curves revealed a FPM of 94+/-11 mg/kg (31% of dose). The portal-arterial differences were negative for 3H-acetate (indicating net extraction) and positive for 14C-ethanol and 14C-acetate (indicating net output). Portal acetate production (extraction plus net output multiplied by the portal plasma flow) increased with time and accounted, over the first 3 hr (82+/-13 mg/kg), for 87% of the FPM. Alcohol oxidation by gastric ADH activity (28.7+/-7.2 mg/kg) accounted for only 31% of the FPM. CONCLUSIONS: The in vivo oxidation of ethanol to acetate in the upper digestive tract accounts for the FPM of ethanol and is mediated, at least in part, by ADH activity.

A gastroenterological list for the millennium.

To determine the 10 most significant advances in gastroenterology during this century as we approach the millennium, the authors polled 50 distinguished active clinicians and leading researchers in the field, including workers in liver disease and the pathology of the gut and its associated glands. Forty-five persons (90%) responded and listed 58 different items. These were then organized into four groups: group A, with 10 categories that received between 42 and 11 votes; group B, with 10 categories that received between 10 and 3 votes; group C, with 3 items receiving 2 votes each; and group D, with the remaining 14 items receiving 1 vote each. The respondents did not indicate their choices in rank order. The top 10 leading choices (group A, containing between 42 and 11 votes) included Helicobacter pylori, fiberoptic endoscopy, gastrointestinal imaging by radiograph and computed tomographic scan, Australia antigen including vaccines for hepatitis A and B, the molecular basis of colon cancer, liver transplantation, laparoscopic-assisted surgery, therapy for peptic ulcer disease including H2-receptor antagonists and proton pump inhibitors, the discovery of gastrointestinal hormones beginning with secretin, and lastly the discovery of the role for gluten in celiac disease.