Mechanism of the aspirin-induced rise in blood alcohol levels.

Aspirin increases blood alcohol levels after post-prandial alcohol consumption in men. This was attributed to a decrease in first pass metabolism secondary to inhibition of gastric alcohol dehydrogenase. Since accelerated gastric emptying, decreased volume of distribution or delayed elimination could also result in higher blood alcohol levels, we investigated the effect of aspirin (1 g taken with a meal) on these parameters. Aspirin did not change the volume of ethanol distribution or the rate of its elimination. Moreover, it did not have a significant effect on gastric emptying. The half-time of 99Tc-DTPA loss was 65.5+/-5.4 minutes without and 71.3+/-6.5, with aspirin. Despite a trend for slower gastric emptying with aspirin, the alcohol bioavailability increased and was associated with a 39% decrease in the first pass metabolism of alcohol (from 106+/-4 to 65+/-19 mg/kg, p<0.05), consistent with the inhibition of gastric ADH activity. In keeping with this interpretation, the effect of aspirin was virtually absent in women, who have a much smaller first pass metabolism available for inhibition by aspirin.

Metabolism of alcohol by human gastric cells: relation to first-pass metabolism.

BACKGROUND & AIMS: The bioavailability of orally administered alcohol is incomplete, indicating first-pass metabolism. There is debate regarding the site of first-pass metabolism and specifically whether the stomach has the metabolic capacity to account for first-pass metabolism. The aim of this study was to assess ethanol metabolism by human gastric mucosa cells in primary culture. METHODS: Cells were incubated with [1-14C]ethanol, and the quantity of ethanol oxidized was measured by the production of [1-14C]acetate. RESULTS: Gastric cells cultured from men produced 7.3 +/- 3.5 mumol acetate.10(6) cells-1.h-1, which was more than that generated in cells from women (3.2 +/- 0.6; P < 0.05). Acetate production was inhibited by 4-methylpyrazole (a class I alcohol dehydrogenase [ADH] inhibitor) and by m-nitrobenzaldehyde (a selective substrate for class IV ADH isoenzyme) but not by sodium azide (a catalase inhibitor). Cimetidine (a gastric ADH inhibitor) reduced acetate production by as much as 59%, whereas ranitidine had no significant effect. CONCLUSIONS: Human gastric cells metabolize sufficient alcohol to account for the bulk of first-pass metabolism. At least two isozymes of gastric ADH contribute to this metabolism. Cimetidine, but not ranitidine, inhibits gastric alcohol metabolism in keeping with its inhibition of in vivo first-pass metabolism.

Gastric metabolism of ethanol in Syrian golden hamster.

First-pass metabolism (FPM) of orally ingested alcohol has been attributed to gastric alcohol dehydrogenase (ADH) activity in both humans and rats. To determine whether gastric alcohol dehydrogenase is essential for alcohol FPM, we sought a species lacking this enzyme. We found that Syrian golden hamsters have negligible gastric ADH yet alcohol FPM (265 +/- 25 mg ethanol/kg) was comparable to that of rats (251 +/- 31 mg/kg). To determine whether hamster gastric mucosal cells metabolize sufficient alcohol to account for this FPM, primary cultures were established, and these cells metabolized 1.99 +/- 0.84 mumol ethanol/10(6) cells/hr, an amount sufficient to account for the bulk of alcohol FPM. In contrast to alcohol dehydrogenase, catalase activity in hamster gastric mucosa (870 +/- 93 units/g tissue) was eightfold higher than in rat gastric mucosa (111 +/- 9 units/g tissue; P < 0.0001). FPM in hamsters treated with 3-aminotriazole was reduced from 242 +/- 24 to 130 +/- 22 mg/kg (P < 0.05) but was not reduced in rats. The results imply that catalase participates in gastric alcohol metabolism of hamsters.

First-pass metabolism of alcohol. Absence of diurnal variation and its inhibition by cimetidine after evening meal.

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.

Metabolism of ethanol in rat gastric cells and its inhibition by cimetidine.

BACKGROUND/AIMS: Several studies have shown that the stomach has sufficient alcohol dehydrogenase activity to metabolize a significant amount of alcohol and that cimetidine depresses this alcohol dehydrogenase activity. However, both gastric metabolism of ethanol and its inhibition by cimetidine remain controversial. Given the difficulty in assessing gastric metabolism of ethanol in vivo, this subject was investigated in vitro. METHODS: Cultured rat gastric epithelial cells were incubated with 200 mmol/L [1-14C]ethanol for 90 minutes with and without cimetidine (0.1-1 mmol/L) or omeprazole (1 mmol/L). The quantity of ethanol oxidized by gastric cells was measured by the amount of acetate produced using ion exchange chromatography. RESULTS: The majority of cells at confluency had typical features of mucous cells. The gastric cells metabolized significant amounts of ethanol, sufficient to account for in vivo first-pass metabolism of ethanol in rats. Cimetidine, but not omeprazole, reduced ethanol metabolism by 39.9% +/- 4.9% (P < 0.01), an inhibition comparable with that previously reported for first-pass metabolism in vivo. CONCLUSIONS: Gastric cells in tissue culture are capable of significant ethanol oxidation, the in vitro rates are sufficient to account for first-pass metabolism of ethanol in vivo, and cimetidine inhibits ethanol metabolism in tissue culture, an effect that parallels its decrease of first-pass metabolism in vivo.

Helicobacter infection and gastric ethanol metabolism.

The organism frequently colonizing the stomach of patients suffering from chronic active gastritis and peptic ulcer disease--Helicobacter pylori--possesses marked alcohol dehydrogenase (ADH) activity. Consequently, Helicobacter infection may contribute to the capacity of the stomach to metabolize ethanol and lead to increased acetaldehyde production. To study this hypothesis, we first determined ADH activity in a variety of H. pylori strains originally isolated from human gastric mucosal biopsies. ADH activity was also measured in endoscopic gastric mucosal specimens obtained from H. pylori-positive and -negative patients. Furthermore, we used a mouse model of Helicobacter infection to determine whether infected animals exhibit more gastric ethanol metabolism than noninfected controls. Most of the 32 H. pylori strains studied possessed clear ADH activity and produced acetaldehyde. In humans, gastric ADH activity of corpus mucosa did not differ between H. pylori-positive and -negative subjects, whereas in antral biopsies ADH activity was significantly lower in infected patients. In mice, gastric ADH activity was similar or even lower in infected animals than in controls, depending on the duration of infection, despite the fact that the infectious agent used--Helicobacter felis--showed ADH activity in vitro. In accordance with this, Helicobacter infection tended to decrease rather than increase gastric ethanol metabolism in mice. In humans, it remains to be established whether the observed decrease in antral ADH activity associated with H. pylori infection can lead to reduced gastric first-pass metabolism of ethanol.

Bioavailability of alcohol: role of gastric metabolism and its interaction with other drugs.

In most individuals, only part of the imbibed alcohol reaches the systemic blood. With doses relevant to social drinking, this is due mainly to gastric first-pass metabolism of alcohol, which acts as a barrier against toxic alcohol blood levels. The activity of gastric alcohol dehydrogenase can account for a substantial fraction of this metabolism. Fasting, female gender, old age, dilution of alcoholic beverages, chronic alcohol consumption and still undetermined factors decrease the gastric metabolism of alcohol. Aspirin and some H2-receptor antagonists also inhibit this gastric activity. In subjects with documented first-pass metabolism, these drugs increase blood alcohol levels, especially after repeated small drinks, and may result in unexpected impairment to perform complex tasks, such as driving. Thus, patients treated with these drugs should be warned of this possible side effect.

First pass metabolism of ethanol.

The human stomach has both low and high K(m) ADH isozymes, resulting in significant ethanol metabolism in gastric cells in vitro, and decreased bioavailability of ethanol (first pass metabolism: FPM) in vivo. Intraduodenal or intraportal infusion of amounts of ethanol equivalent to those emptied into the duodenum or disappearing from pylorus-ligated stomachs produced significantly higher blood levels than intragastric administration, whereas portal ligation had no effect, documenting the role of gastric ethanol metabolism in vivo. This "protective barrier" against the systemic effects of ethanol disappears after gastrectomy and is partly lost in the alcoholic because of accelerated gastric emptying and decreased gastric ADH activity, respectively. The latter is also lower in women than in men, at least below the age of 50. Some ADH isozymes require a relatively high ethanol concentration for optimal activity; therefore, the concentration of alcoholic beverages affects the amount metabolized. Fasting strikingly decreases FPM, most likely because of accelerated gastric emptying, resulting in shortened exposure of ethanol to gastric ADH and its more rapid intestinal absorption. Commonly used drugs, such as aspirin, acetaminophen and some H2-blockers decrease gastric ADH activity in vitro and produce increased blood alcohol levels in vivo, particularly at a low alcohol dose, equivalent to social drinking. Effects at higher ethanol dosage are still the subject of controversy. However, not all subjects display significant FPM, and published negative reports with H2 blockers do not specify whether first pass metabolism was present to begin with; some of the negative investigations also used dilute concentrations of alcohol, shown to minimize gastric metabolism. Thus, the stomach can metabolize amounts of ethanol of clinical relevance, an effect which is attenuated by various drugs, resulting in increased blood levels.

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.

Comparison of blood alcohol concentrations after beer and whiskey.

To determine whether blood alcohol concentrations achieved by ingestion of various alcoholic beverages differ as a function of prandial state, healthy male volunteers, aged 24 to 48 years, were given the same amount of alcohol (0.3 g/kg) as different beverages. The alcohol was consumed in three prandial states: postprandial (1 hr after a meal, n = 10), prandial (during the meal, n = 10), and preprandial (after an overnight fast, n = 9). Each subject was tested with both beer and whiskey, and in the postprandial state also with wine and sherry, in a within-subjects design. Blood alcohol concentrations were estimated by breath analysis for 4 hr or until concentrations reached zero. Peak blood alcohol levels were higher with beer than with whiskey in the postprandial and prandial conditions (p < 0.01), whereas the opposite was true in the preprandial state (p < 0.05). Similarly, the area under the blood alcohol curve was higher with beer in the prandial state (p < 0.05), and higher with whiskey in the preprandial condition (p < 0.01). Wine and sherry yielded peak concentrations intermediate between those of beer and whiskey in the postprandial state. The results indicate that a dilute alcoholic drink can yield either higher or lower blood alcohol levels than a concentrated beverage, depending on the prandial state.

Effects of ranitidine on blood alcohol levels after ethanol ingestion. Comparison with other H2-receptor antagonists.

OBJECTIVE: To determine whether the H2-receptor antagonist, ranitidine, which is a potent inhibitor of gastric alcohol dehydrogenase activity in vitro, increases the bioavailability of orally administered ethanol (0.3 g/kg of body weight) and to compare the resulting blood alcohol concentrations with those of two other H2-antagonists, cimetidine and famotidine, the latter of which does not inhibit gastric alcohol dehydrogenase. DESIGN: For each of the H2-receptor antagonists, a different group of subjects was used. In each group, a paired design was adopted with each subject serving as his own control. SETTING: Hospital laboratory. SUBJECTS: Normal, healthy men aged 24 to 46 years. INTERVENTION: Eight men were treated for 1 week with ranitidine (300 mg/d), six with cimetidine (1000 mg/d), and six with famotidine (40 mg/d). MEASURES: Peak blood alcohol concentrations, areas under the blood alcohol curve, first-pass metabolism, and bioavailability of orally consumed ethanol. RESULTS: Relative to baseline, ranitidine increased the mean peak concentration and the area under the curve of blood alcohol concentrations by 34% (P less than .05) and 41% (P less than .01), respectively. First-pass metabolism of ethanol was decreased from 70 +/- 10 to 31 +/- 9 mg/kg of body weight, with a corresponding increase in ethanol bioavailability of 79.6% to 92.6%. By comparison, cimetidine had even a greater effect on blood alcohol levels, while famotidine had no significant effects. CONCLUSION: Patients treated with ranitidine or cimetidine should be warned of possible functional impairments after consumption of amounts of ethanol considered safe in the absence of such therapy.

Effect of concentration of ingested ethanol on blood alcohol levels.

The effect of the concentration of ingested ethanol on the resulting blood alcohol concentrations (BAC) was tested in both humans and rats. In humans, when 0.3 g/kg body weight ethanol was ingested postprandially, the mean area under the blood alcohol curve (AUC) and the mean peak BAC were significantly lower with a concentrated (40% w/v) than with a dilute (4%) solution. Similarly, rats in the fed state exhibited decreasing mean AUCs with increasing concentrations (4%, 16%, and 40%) of intragastrically administered ethanol (1.0 g/kg). Pharmacokinetic analysis comparing intragastric and intraperitoneal administration of ethanol to rats indicated that the more concentrated solution resulted in less alcohol reaching the systemic circulation (4%: 0.896 +/- 0.074 g/kg: 16% 0.772 +/- 0.072 g/kg; 40%: 0.453 +/- 0.037 g/kg) and suggested that this affect could be attributed to two factors: increased gastric retention of ethanol (4%: 0.109 +/- 0.024 g/kg; 16%: 0.102 +/- 0.016 g/kg; 40%: 0.214 +/- 0.042 g/kg) and a large increase in first-pass metabolism (4%; 0.004 +/- 0.054 g/kg; 16%: 0.145 +/- 0.048 g/kg; 40%: 0.329 +/- 0.044 g/kg). In contrast to the results in the fed state, in humans fasted overnight the concentration of alcohol consumed (4%, 16%, and 40%) had no significant effect on mean AUCs. In fasted rats, mean AUCs after intragastric intubation of the two lower concentrations of ethanol (4% and 16%) were comparable to those found after intraperitoneal injection, and only the highest ethanol concentration (40%) produced a lower mean AUC.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin increases blood alcohol concentrations in humans after ingestion of ethanol.

Gastric first-pass metabolism of ethanol is an important determinant of blood alcohol concentrations. We studied five healthy volunteers after ingestion of ethanol (0.3 g/kg of body weight) and found that blood alcohol concentrations in the fed state (ie, 1 hour after a standard breakfast) were significantly higher when the subjects received 1 g of aspirin 1 hour before ingestion of ethanol than without the drug. In vitro, aspirin clearly decreased the activity of gastric alcohol dehydrogenase in human subjects and in rat models, but not that of hepatic alcohol dehydrogenase in rats. Furthermore, blood alcohol concentrations in rats were unaffected by ingestion of aspirin when ethanol was infused intravenously. Thus, aspirin may increase the bioavailability of ingested ethanol in humans, possibly by reducing ethanol oxidation by gastric alcohol dehydrogenase.

Manipulation of alcohol preference in C57BL/6J mice by episodes of food poisoning.

Individual differences in the amount of alcohol consumed in a choice situation are found in highly inbred C57BL/6J mice. The extent to which environmental stress can modify alcohol preference was studied by coupling acute episodes of poisoning with restricted fluid availability, and recovery with free choice of drinking fluids. Addition of actinomycin D, a mycotoxin, to ordinary chow during 2-day periods produced acute episodes of nonlethal food poisoning from which the mice recovered rapidly. Consumption of a 10% alcohol solution and of water was recorded for several weeks before poisoning and for several weeks after the last episode. By varying drinking fluids available to the mice during the episodes of poisoning, long-lasting changes in alcohol preference were produced. When 10% alcohol was the sole drinking fluid available during poisoning, preference for the alcohol solution was abolished. When water was the sole fluid during poisoning, alcohol preference was increased above the already high levels established in the baseline and above a control group that was restricted to water during the treatment periods but was not poisoned. This increased alcohol preference was due to a nearly complete suppression of water intake in the posttreatment period; there was no significant increase in amount of alcohol consumed. The greatest individual differences in subsequent alcohol preference were found in the group of mice which continued to have free choice of alcohol and water during episodes of poisoning. The variety of responses to the same treatment show how environmental influences outside the experimenter's control may account for the variability found in voluntary alcohol consumption among genetically homogeneous mice.

Toward an analogue of alcoholism in mice: analysis of nongenetic variance in consumption of alcohol.

Drinking behavior of the isogenic mouse strain C57BL/6J was analyzed into nongenetic components: stochastic fluctuations, responses to fluctuations in the current environment, and persistent differences between individual animals. The latter accounted for the major part of the variance. The variance was neither increased by differences in diet during the postweaning rapid growth period (prior to assay for drinking choice) nor diminished by uniformity of treatment during this period, suggesting that significant differentiation had occurred prior to weaning. The large variance between animals could be explained by assuming that the genetic role in consumption of alcohol by C57BL mice is permissive--a relative insensitivity to the aversive orosensory and pharmacological effects of 10% alcohol--rather than a specific drug-seeking predisposition.

Why does a sucrose choice reduce the consumption of alcohol in C57BL/6J mice?

To determine why animals reject alcohol when offered palatable solutions of sucrose, male C57BL/6J mice were challenged first with 5% sucrose then with 10% sucrose, while given continuous free-access to alcohol and water. The 5% sucrose dramatically reduced the intake of alcohol and increased the intake of total fluid by an average of 7.3 ml/day. The suppression of alcohol intake could not be attributed to a volumetric ceiling since access to 10% sucrose produced a further large increase in total intake (8.8 ml/day). The results support the interpretation that animals consume alcohol for characteristics it shares with sucrose.