Acute tolerance during intravenous infusion of alcohol: comparison of performance during ascending and steady state concentrations--a pilot study.

Although acute tolerance (AT) to alcohol has been demonstrated in many single-dose studies, the existence of AT at steady state concentrations of alcohol has been questioned. In the present study, six subjects were examined as (1) 7.5% alcohol or (2) placebo was administered intravenously (IV). The order of the infusions was randomized. The alcohol infusions were designed to result in similar blood alcohol concentrations at 20, 60, and 140 min (approximately 0. 7 per thousand). At 20 min, the concentrations were rising; the steady state (+/-0.10 per thousand) was reached after 60 min and continued until 140 min. Three reaction time (RT) tests from the automated psychological test system were used (simple RT, two-choice RT, and two-choice RT with auditory inhibition). When the performance of the subjects was compared at rising and steady-state concentrations of alcohol, AT was shown for the most complex task requiring parallel processing, i.e., RT with failed inhibition, test. However, at steady state (i.e., 60 vs. 140 min), AT was not found for any of the tests. Further, the analysis showed that the test results of different individuals were related to their estimated normal alcohol consumption and that these differences presumably influenced the test results in accordance with our earlier findings.

Metabolic interaction between endogenous methanol and exogenous ethanol studied in human volunteers by analysis of breath.

Ethanol was administered to 5 healthy volunteers by intravenous infusion to maintain a constant blood-alcohol concentration (BAC) of about 0.8 mg/ml (17.4 mmol/l) for 3-4 hr. Before starting the infusion and at 15 min. intervals thereafter, we analysed end-expired air by a highly sensitive gas chromatographic method. The presumed concentrations of ethanol and methanol in blood were estimated indirectly from measurements in the breath. The liquid/air partition coefficients of methanol were determined for whole blood, plasma, water, and corn-oil when dilute solutions were equilibrated at 34 degrees and 37 degrees. The results at 37 degrees were 2709 +/- 165, 3400 +/- 86, 2948 +/- 221 and 44.5 +/- 6.3 for whole-blood/air, water/air, plasma/air and corn-oil/air respectively. During infusion of ethanol, the concentrations of endogenous methanol in blood rose from being between 0.4-0.8 mg/l to reach between 1.2-3.4 mg/l with a substantial inter-subject variation in rate of increase. Our results confirm the existence of endogenous methanol in human blood and breath and demonstrate that the concentrations present can rise to abnormally high levels when the body is flooded with exogenous ethanol.

Mechanism and regulation of ethanol elimination in humans: intermolecular hydrogen transfer and oxidoreduction in vivo.

Ethanol metabolism was studied in four healthy volunteers by intravenous infusion of a mixture of [1,1-2H2]ethanol (1.0 mmol/kg) and [2,2,2-2H3]ethanol (1.0 mmol/kg) followed by blood sampling at 10-min intervals. The concentrations of ethanols labeled with 1, 2, 3, and 4 deuterium atoms were determined by gas chromatography/mass spectrometry of the 3,5-dinitrobenzoates. During the first 30 min mono- and tetradeuteriated molecules appeared rapidly, which indicates that a fraction of the ethanol was formed from acetaldehyde by exchange. This fraction was calculated to be 38-58% and the hydrogen incorporated during the reduction was mainly (63-82%) derived from C-1 of ethanol, indicating slow exchange of enzyme-bound NADH. After 30 min the elimination followed first-order kinetics with t1/2 of 18-31 min and with a small primary isotope effect (1.05-1.11). This indicates almost complete removal of ethanol from blood passing through the liver when the concentration is low (below 1 mM). The results indicate that as long as hepatic blood flow is not limiting, the rate of alcohol dehydrogenase-catalyzed elimination of a small dose of ethanol in vivo is limited by the dissociation of NADH from the enzyme and by the rates of oxidation of acetaldehyde and reoxidation of NADH.

Time course of breath acetaldehyde concentrations during intravenous infusions of ethanol in healthy men.

A gas chromatographic method was developed for the quantitative determination of acetaldehyde in expired alveolar air of human subjects. A rapid and direct gas-sampling system allow serial determinations and avoid the need for correcting for sample losses or poor recoveries. This method was evaluated in experiments with healthy men during different modes of intravenous infusion of ethanol. The time course of breath-ethanol and breath-acetaldehyde concentrations were used to estimate the coexisting blood levels. Blood acetaldehyde concentration (y) was about 2000 times less than blood ethanol (x) and the values were highly correlated r = 0.90 +/- 0.05, P less than 0.001. The regression equation was y = 2.0 + 0.303x; the intercept was significantly different from zero. Breath acetaldehyde faithfully followed the changes in breath and blood ethanol concentrations for widely varying rates of ethanol infusion.