Rate Of Ethanol Disappearance Research Articles

Individual Differences in Blood Alcohol Concentrations after Moderate Drinking Are Mainly Regulated by Gastric Emptying Rate Together with Ethanol Distribution Volume

Blood alcohol concentration (BAC) differs greatly among individuals, even when people of the same sex and age drink alcohol under the same drinking conditions. In this study, we investigated the main factors involved in the internal reg-ulation of individual differences in BAC, focusing on the alcohol dehydrogenase 1B (ADH1B) genotype, blood acetal-dehyde concentration (BAcH), amount of habitual alcohol consumption, pharmacokinetic parameters of BAC, distribution volume of ethanol (Vd), and gastric emptying rate (GER) under the same drinking conditions. Twenty healthy Japanese males aged between 40 and 59 years old and having the aldehyde dehydrogenase 2 (ALDH2) genotype of ALDH 2*1/*2 were recruited for this study. The subjects were given 0.32 g ethanol/kg body weight in the form of commercially available beer (5%, v/v). The results showed that BAC-max differed greatly among individuals with a more than two-fold variation. When the BAC-time curve was compared among ADH1B genotypes (ADH1B*1/*1, *1/*2, and *2/*2), there were no differences in BAC among the genotypes. Although BAcH, monthly alcohol consumption, elimination rate of blood ethanol (β value) and ethanol disappearance rate from the body (EDR) can affect BAC, all of them had no correlations with BAC-max. However, Vd (liter/kg), ΔPlasma glucose concentration (ΔPGC = PGC30 min ? PGC0 min) and the serum concentration of gastric inhibitory polypeptide (GIP) did correlate with BAC-max. Model 2 in multiple linear regression analysis showed the optimal model for Vd and GIP with positive correlations with BAC-max. As GIP and ΔPGC are both reflected by gastric emptying rate (GER), we concluded that the individual differences in BAC after moderate drinking are mainly regulated by GER together with Vd. These findings demonstrate that together with body water content, the gastrointestinal tract plays an important role in the regulation of individual differences in BAC, involving first pass metabolism of ethanol.

ENHANCED RATE OF ETHANOL ELIMINATION FROM BLOOD AFTER INTRAVENOUS ADMINISTRATION OF AMINO ACIDS COMPARED WITH EQUICALORIC GLUCOSE

To investigate the effect of an amino acid mixture given intravenously (i.v.) on the rate of ethanol elimination from blood compared with equicaloric glucose and Ringer's acetate as control treatments. In a randomized cross-over study, six healthy men (mean age 23 years) fasted overnight before receiving either Ringer's acetate, glucose or the amino acid mixture (Vamin 18 g N/l) by constant rate i.v. infusion over 4.5 h. Ethanol (0.4 g/kg) was given by an i.v. infusion lasting 60 min during the time each of the treatments was administered. At various times post-infusion, blood samples were taken for determination of ethanol by headspace gas chromatography. Blood glucose and heart rate were monitored at regular intervals. Concentration-time profiles of ethanol were plotted for each subject and the rate of ethanol disappearance from blood as well as other pharmacokinetic parameters were compared by repeated measures analysis of variance. The rate of ethanol elimination from blood was increased significantly (P < 0.001) after treatment with amino acids (mean +/- SD, 0.174 +/- 0.011 g/l/h) compared with equicaloric glucose (0.121 +/- 0.016 g/l/h) or Ringer's acetate (0.110 +/- 0.013 g/l/h). Heart rate was also slightly higher during infusion of the amino acid mixture (P < 0.05). When the rate of ethanol elimination from blood is relatively slow, such as after an overnight fast, it can be increased by approximately 60% after treatment with i.v. amino acids. The efficacy of amino acid treatment was not related to the supply of calories because glucose was no more effective than Ringer's acetate. We suggest that amino acids might increase hepatic oxygen consumption, resulting in a more effective conversion of NADH to NAD+ in mitochondria. An important feature of the experimental design was ensuring hepatic availability of amino acids during much of the time that ethanol was being metabolized.

Comparison of ethanol concentrations in venous blood and end-expired breath during a controlled drinking study

Concentration–time profiles of ethanol were determined for venous whole blood and end-expired breath during a controlled drinking experiment in which healthy men ( n=9) and women ( n=9) drank 0.40–0.65 g ethanol per kg body weight in 20–30 min. Specimens of blood and breath were obtained for analysis of ethanol starting at 50–60 min post-dosing and then every 30–60 min for 3–6 h. This protocol furnished 130 blood–breath pairs for statistical evaluation. Blood-ethanol concentration (BAC, mg/g) was determined by headspace gas chromatography and breath-ethanol concentration (BrAC, mg/2 l) was determined with a quantitative infrared analyzer (Intoxilyzer 5000S), which is the instrument currently used in Sweden for legal purposes. In 18 instances the Intoxilyzer 5000S gave readings of 0.00 mg/2 l whereas the actual BAC was 0.08 mg/g on average (range 0.04–0.15 mg/g). The remaining 112 blood- and breath-alcohol measurements were highly correlated ( r=0.97) and the regression relationship was BAC=0.10+0.91BrAC and the residual standard deviation (S.D.) was 0.042 mg/g (8.4%). The slope (0.91±0.0217) differed significantly from unity being 9% low and the intercept (0.10±0.0101) deviated from zero ( t=10.2, P<0.001), indicating the presence of both proportional and constant bias, respectively. The mean bias (BAC − BrAC) was 0.068 mg/g and the 95% limits of agreement were −0.021 and 0.156 mg/g. The average BAC/BrAC ratio was 2448±540 (±S.D.) with a median of 2351 and 2.5th and 97.5th percentiles of 1836 and 4082. We found no significant gender-related differences in BAC/BrAC ratios, being 2553±576 for men and 2417±494 for women ( t=1.34, P>0.05). The mean rate of ethanol disappearance from blood was 0.157±0.021 mg/(g per hour), which was very close to the elimination rate from breath of 0.161±0.021 mg/(2 l per hour) ( P>0.05). Breath-test results obtained with Intoxilyzer 5000S (mg/2 l) were generally less than the coexisting concentrations of ethanol in venous blood (mg/g), which gives an advantage to the suspect who provides breath compared with blood in cases close to a threshold alcohol limit.

Pharmacokinetic study of ethanol and its metabolites in culture cells

We examined the disposition of ethanol, acetaldehyde and acetate in culture cells. Rat hepatoma-derived cells, H4IIE, were grown in T-shaped flasks to confluence in minimal essential medium supplemented with 5% fetal bovine serum. For the experimental group, the medium in the flask was replaced with a medium containing a 0, 4, 8 or 20 mM ethanol solution. For the control group, cell-free flasks containing media of the same ethanol concentrations were used. The ethanol, acetaldehyde and acetate concentrations in the flask were measured periodically by headspace gas chromatography. We found that the ethanol concentration of the medium decreased in both the control and the experimental groups; however, the rate of ethanol disappearance differed between these two groups, suggesting that ethanol is metabolized in the culture cells, and that its metabolism is saturated at a lower concentration. The acetaldehyde level was usually markedly low. Acetate was produced both with and without ethanol treatment, but the rate of acetate production increased with ethanol treatment, indicating that a certain percentage of acetate leaks into the medium. These findings suggest that ethanol in culture cells behaves in a kinetic fashion in vivo.

Ethanol metabolism in patients with liver cirrhosis

Aspects of human metabolism of ethanol are reviewed with the main focus on the rate of ethanol clearance from blood in patients suffering from liver cirrhosis. Studies in humans and experimental animals do not support the notion of a slower rate of ethanol metabolism in patients with liver cirrhosis compared with those with normal liver function. The rate of ethanol disappearance from blood in healthy non-alcoholic subjects falls within the range 9-20 mg/dL/h and there is no compelling evidence to suggest that this should be much different in cirrhotic patients.

The drunkest drinking driver in Sweden: blood alcohol concentration 0.545% w/v.

This article examined drinking drivers (N = 81) who had unusually high blood alcohol concentrations (BAC > or = 0.400% w/v) when apprehended. These drinking drivers were investigated in relation to age, gender, weekday and time of day of arrest, amount of alcohol in the body and the rate of disappearance of alcohol from the blood. The concentration of ethanol in whole blood was determined in triplicate by headspace gas chromatography and the rate of disappearance of ethanol (burn-off rate) was calculated when two blood specimens were taken about 1 hour apart (mean = 65 minutes, range = 33-110 minutes). Seven of the 81 drunk drivers were women (9%) with a mean age of 40 years (range = 29-52 years) and 74 were men (91%) with a mean age of 44 years (range = 28-68 years). The mean, median and range of BACs for the women were 0.422% w/v, 0.413% w/v and 0.403-0.451% w/v, compared with BACs of 0.425% w/v, 0.416% w/v and 0.400-0.545% w/v for the men, respectively (p > .05). The BAC was not dependent on subjects' age (F = 1.04, 7/73 df, p > .05) nor the weekday when they were apprehended (F = 1.62, 6/74 df, p > .05). Most drunk drivers (49%) were apprehended between 12 noon and 6 PM, 40% were involved in traffic accidents and 17% did not hold a valid driving license. The mean (+/-SD) disappearance rate of ethanol from blood was 0.023% +/- 0.01% w/v per hour (N = 26), with a range of 0.013 to 0.061% w/v per hour. Drinking alcohol to reach a BAC of 0.400% w/v or more and attempting to drive a motor vehicle indicates an exceptionally high cellular tolerance to the impairment caused by this drug. The alcohol burn-off rate was relatively high in these heavy drinkers (mean = 0.023% w/v per hour), which probably reflects the development of metabolic tolerance as well.

Effects of repeated cocaine administration on alcohol consumption.

Alcohol consumption (alcohol preference or alcohol intake) in animals is an index of human drinking behavior. Cocaine is the most frequently abused drug at present. Therefore, an increasing number of cases demonstrating concurrent use of alcohol and cocaine is being noted. We examined whether cocaine affects alcohol consumption and studied the mechanism of change in alcohol consumption following cocaine administration. We measured alcohol consumption in inbred mice, C57BL/6J and C3H/HeJ, when 10 or 50 mg/kg cocaine was administered intraperitoneally once a day for 1 week. Then the rate of blood ethanol disappearance from C57BL/6J mice in vivo was measured. Also, liver alcohol dehydrogenase(ADH) and aldehyde dehydrogenase(ALDH) activity in vitro were measured in the C57BL/6J mice. Following 50 mg/kg cocaine administration, alcohol consumption was reduced in C57BL/6J mice, but there was no clear change in C3H/HeJ mice. The rate of blood ethanol disappearance was not changed by pretreatment with cocaine. Neither liver ADH nor ALDH activity was changed by repeated cocaine administration. The present study showed that repeated cocaine administration decreased alcohol consumption in C57BL/6J mice without altering the metabolism of ethanol.

Pharmacokinetics of ethanol in patients with renal failure before and after hemodialysis

We studied the pharmacokinetics of ethanol in seven patients suffering from terminal renal failure before and after they underwent hemodialysis. Ethanol (0.40 g/kg) was administered in the morning after an overnight fast by a constant rate intravenous (IV) infusion over 45 min. After removing a mean fluid volume of 2.46±0.48 liters (±SD), span 1.76–3.43 liters by hemodialysis, the same subjects received a second IV infusion of ethanol after they had eaten lunch. At exactly timed intervals of 0, 45, 90, 105, 120, 135, 150, 165, and 180 min from the start of the infusion, two blood-samples were drawn and the plasma portion of one of them was obtained by centrifugation. The concentration of ethanol in blood and plasma was determined by headspace gas chromatography and the water-content of whole blood was determined from the change in weight after desiccation. Plasma always contained a higher concentration of ethanol than whole blood and the mean plasma/whole blood ratio in patients with renal failure was 1.07:1 (span 1.05–1.10). The rate of ethanol disappearance from blood ( β-slope) was faster (0.185±0.013 versus 0.157±0.022 g/l/h), the C 0 value was higher (0.79±0.08 versus 0.73±0.10 g/l) and the apparent volume of distribution ( V d) of ethanol was lower (0.507±0.049 versus 0.558±0.078 l/kg) after hemodialysis. The water content of whole blood was significantly higher ( P<0.001) before dialysis (88.6±1.97 g/100 ml) compared with after dialysis (87.4±2.01 g/100 ml). The higher V d for ethanol and lower C 0 as well as higher blood-water content are to be expected for a over hydrated condition before hemodialysis. The swifter rate of ethanol elimination from blood ( β-slope) after hemodialysis should be interpreted with caution because eating a meal before the second infusion of ethanol is a confounding factor. Nevertheless, the rate of elimination of ethanol from blood in patients with renal failure agreed reasonably well with values expected for healthy subjects, namely mean 0.15 g/l/h spanning from 0.10 to 0.20 g/l/h.

Concentration-Time Profiles of Ethanol in Arterial and Venous Blood and End-Expired Breath During and After Intravenous Infusion

Ethanol (0.40 g/kg) was administered to 13 healthy men by intravenous (i.v.) infusion at a constant rate for 30 min. The concentrations of ethanol in arterial blood (ABAC), venous blood (VBAC), and end-expired breath (BrAC) were measured at 17 exactly timed intervals. Blood-ethanol was determined by headspace gas chromatography and breath-ethanol was measured with a quantitative infrared analyzer (DataMaster). BrAC was multiplied by 2300 to estimate the concentrations of alcohol in blood. During the infusion of ethanol, ABAC exceeded VBAC by about 10 mg/dL on the average and ABAC was also higher than BrAC x 2300 by about 4 mg/dL on average. When infusion of alcohol ended, ABAC, VBAC, and BrAC were 94.8 +/- 2.06 (+/- SE), 84.7 +/- 1.54, and 89.3 +/- 2.10 mg/dL, respectively. The concentrations of alcohol in blood (ABAC and VBAC) and breath decreased abruptly after the administration of alcohol stopped and by 5 min postinfusion, the A-V differences in concentration of ethanol were small or negligible. The mean apparent half-life of the distribution plunge was 7 to 8 min, being about the same for ABAC, VBAC, and BrAC. The disappearance rate of ethanol was 15.5 +/- 0.55 mg/ dL/h (mean +/- SE) for arterial blood, 15.2 +/- 0.49 mg/dL/h for venous blood, and 16.3 +/- 0.73 mg/230 L/h for breath; no significant differences were noted (p > 0.05). We conclude that A-V differences in the concentration of ethanol exist during the loading phase but are rapidly abolished when the administration of ethanol terminates. In the post-absorptive phase of ethanol kinetics, when alcohol has mixed with the total body water, VBAC exceeds ABAC by about 1-2 mg/100 mL on average.

Acceleration of the alcohol oxidation rate in rats with aloin, a quinone derivative of Aloe

Aloe contains abundant aloin, a C-glycoside derivative of anthraquinone. Based on recent reports indicating that the water extract of Aloe enhances the ethanol oxidation rate and also that quinones, in general, have a functional role in elevating the alcohol oxidation rate in vivo, we have attempted to identify the quinone derivative contained in Aloe that could increase the alcohol oxidation rate. Upon oral administration of aloin (300 mg/kg) given 12 hr prior to the administration of alcohol (3.0 g/kg), the blood alcohol area under the curve (AUC) was found to be decreased significantly (by 40%). This was supported by increases in the rates of blood alcohol elimination and the disappearance of alcohol from the body by 45 and 50%, respectively. Analysis of hepatic triglyceride (TG) levels revealed that both the ethanol and the aloin treatment alone significantly increased the TG levels in a comparable manner; however, the level obtained by the combined treatment of aloin and ethanol was not statistically different from that produced by either treatment alone. The levels of serum L-aspartate:2-oxoglutarate aminotransferase (AST) and L-alanine:2-oxoglutarate aminotransferase (ALT) activities were not increased by acute alcohol intoxication, aloin alone, or by the combined treatment of alcohol and aloin. Pretreatments with aloe-emodin, the anthraquinone aglycone of aloin, resulted in a significantly decreased blood alcohol AUC and an increase in the rate of ethanol disappearance. These results suggested that when the aloin localized primarily in the skin of Aloe is ingested, aloe-emodin (the quinone aglycone) may be released, and the released quinone may produce acceleration of the ethanol metabolism rate in vivo.

Multiple steady-states for the oxidation of aqueous ethanol with oxygen on a carbon supported platinum catalyst

The selective oxidation of aqueous ethanol by dioxygen over a platinum on carbon catalyst was investigated in a three-phase continuously stirred tank reactor at a total pressure of 600 kPa, a temperature of 323 K, a pH of 8.4, and a catalyst concentration of 2.3 kg m−3. Multiple steady-states were obtained by systematic changes in the start-up procedure and variation of the feed concentration of ethanol and partial oxygen pressure in the reactor. The ethanol feed concentration was varied from 100 to 2500 mol m−3 and the partial oxygen pressure from 8 to 120 kPa. On the time scale of the experiments, i.e. 21 ks, two steady-states of the net disappearance rate of ethanol are observed in the ethanol feed concentration range from 500 to 2500 mol m−3 at a partial oxygen pressure of 58 kPa and in the range of partial pressure of oxygen from 8 to 120 kPa at an ethanol feed concentration of 500 mol m−3. Three steady-states are observed in the feed ethanol concentration range from 200 to 400 mol m−3 and a partial oxygen pressure of 58 kPa.

Oxidative dehydrogenation of aqueous ethanol on a carbon supported platinum catalyst

The kinetics of the selective oxidative dehydrogenation of ethanol to ethanal over a platinum on graphite catalyst with oxygen in water was investigated in a three-phase continuous stirred tank reactor by variation of temperature, pH and reaetant concentrations. No effect of the pH on the disappearance rate of ethanol was observed. The oxidation proceeds by a sequence in which ethanal and ethanoate are formed successively. The reaction kinetics of the oxidative dehydrogenation of ethanol to ethanal can be described adequately by a relatively simple rate equation based on an irreversible dissociative adsorption of oxygen and an equilibrated dissociative adsorption of ethanol on the same type of sites. The dissociative adsorption of ethanol proceeds by abstraction of the hydroxyl hydrogen. These steps are followed by an irreversible surface reaction between the ethoxy and the oxygen surface species. At typical conditions, i.e. a temperature of 324 K, an ethanol concentration of 500 mol m −3, a pH of 8, and an oxygen partial pressure of 50 kPa, the fractional surface coverages amount to 0.25 for oxygen and 0.11 for both ethoxy species and hydrogen.

Role of Quinone Reductase in in Vivo Ethanol Metabolism and Toxicity

Quinone reductase (QR), in the presence of suitable substrate. results in the regeneration of NAD + from NADH. To test the hypothesis that QR can play a role in ethanol metabolism and toxicity, we studied the effect of a quinone as well as of induced levels of QR on ethanol administered in vivo to male rats and mice. Butylated hydroxyanisole (BHA) is known both to induce QR and to be metabolized to tert-butyl quinone (TBQ). Dietary BHA (0.75% for 10 days), followed by oral ethanol (4 g/ kg, by gavage), increased the rate of ethanol disappearance and decreased the area under the curve (AUC) for blood ethanol in both rats and mice. In addition, BHA pretreatment of rats was shown to prevent ethanol-induced 24-hr hepatic triglyceride accumulation. Also, in rats, TBQ (5 mg/kg, ip) led to decreased AUC and hepatic triglyceride accumulation, although the ethanol disappearance rate was not significantly affected. TBQ in BHA-fed rats resulted in even greater effects on the ethanol disappearance rate and AUC than TBQ or BHA treatment alone. None of these treatment regimens resulted in a significant change in volume of distribution of ethanol. Thus, these results support the hypothesis that induction of QR and/or administration of quinones leads to enhanced in vivo metabolism of ethanol and decreased hepatotoxicity.

Leucine and glucose turnover in chronic alcoholics during early abstinence and after an ethanol load.

We studied leucine turnover using a primed infusion of [1-14C]-L-leucine and glucose turnover using a primed infusion of [6-3H]-D-glucose in five alcoholic patients without liver damage and five age-matched controls. Infusions were maintained for 6 hr, and at the end of the 3rd hour, a 0.8 g/kg iv ethanol load was administered in 20 min. Leucine flux, nonoxidative disposal and oxidation rates, and glucose rate of appearance were calculated during the 3rd and 6th hours of infusion. Ethanol disappearance rate and the percentage completely metabolized to CO2 and H2O in 3 hr were also calculated. Compared with controls, alcoholics had significantly higher basal leucine flux (55.6 +/- 12 vs. 37.3 +/- 9.3 microM/m2/min) and nonoxidative disposal (48.7 +/- 8.7 vs. 31.1 +/- 7.5 microM/m2/min). No differences were observed in basal glucose appearance rates in alcoholics and controls (397.6 +/- 115.2 vs. 349.4 +/- 120.6 microM/m2/min). Compared with controls, alcoholics had a higher alcohol disappearance rate (2.72 +/- 0.59 vs. 1.84 +/- 0.43 mM/kg/min) and percentage of ethanol metabolized to CO2 and H2O in 3 hr (40.6 +/- 10.2 vs. 22.9 +/- 6.9%). After the ethanol load, both leucine turnover and glucose rate of appearance decreased significantly only in alcoholics. There was a positive correlation between the change in leucine flux and ethanol disappearance rate and percentage metabolized to CO2 and H2O in alcoholics.

Disappearance Rate of Ethanol from the Blood of Human Subjects: Implications in Forensic Toxicology

This article outlines major developments in knowledge about the human metabolism of ethanol. The results of a large number of controlled experiments aimed at measuring the rate of ethanol elimination from the blood are reported. The factors that influence the rate of ethanol elimination from blood, such as the amount of ethanol ingested, the drinking habits of the subjects, and the effect of food taken together with, or before, drinking were investigated. The slowest rate of ethanol disappearance was observed in a healthy male subject who ingested 0.68 g ethanol/kg body weight after an overnight (8 h) fast; the beta-slope was 9 mg/dL/h. The fastest rate of ethanol disappearance was observed in a male chronic alcoholic during detoxification; the beta-slope was 36 mg/dL/h. This four-fold difference in the rate of ethanol disposal should be considered when the pharmacokinetics of ethanol become an issue in drinking and driving trials, for example, when retrograde estimations are attempted.

KINETICS OF ETHANOL AND METHANOL IN ALCOHOLICS DURING DETOXIFICATION

We investigated the kinetics of ethanol and methanol in 20 dependent alcoholics (16 men and four women) during the first 24 hr after admission to hospital for detoxification. The blood-ethanol concentration (BEC) on admission ranged from 238 to 489 mg/dl (mean 386 mg/dl). The mean rate of ethanol disappearance from the blood was 23 mg/dl/hr with a spread from 13 to 36 mg/dl/hr. The concentrations of methanol in blood at the start of detoxification ranged from 0.16 to 2.8 mg/dl (mean 1.15 mg/dl) and these levels remained more or less unchanged until the BEC had dropped below 30 mg/dl. The concentrations of ethanol and methanol in blood at the start of detoxification were not correlated (r = 0.032, P > 0.05). The results of this study do not support the notion that the metabolism of methanol in chronic alcoholics proceeds independently of the prevailing BEC. We found a three-fold difference in the rate of disappearance of ethanol from blood in alcohol-dependent subjects.

Effect of Dihydrotestosterone on the Rate of Ethanol Elimination in Healthy Men

Testosterone (T) and, more potently, dihydrotestosterone (DHT), are in vitro inhibitors of hepatic alcohol dehydrogenase (ADH). An increase in the rate of ethanol disappearance (RED) in man has been observed after orchidectomy. We thus investigated the influence of DHT administration on RED in 10 healthy male volunteers. RED was estimated after an oral ethanol bolus (0.6 g/kg), before and after a 14-day treatment with DHT (2 x 125 mg per day percutaneously; Andractim, Besins iscovesco, France). A mean 11.5-fold increase in DHT levels and a 2.0-fold decrease in T values were observed after DHT administration, confirming the good compliance with treatment. RED was decreased after DHT (0.168 +/- 0.043 vs. 0.137 +/- 0.043 g/l/hr; mean +/- SD; p less than 0.01 using Wilcoxon's paired comparison test). These data are consistent with a DHT-induced inhibition of hepatic ADH in vivo. This could have a beneficial effect by decreasing acetaldehyde production in alcoholic patients, in whom marked hypoandrogenism frequently occurs.

Changes in ethanol concentration during incubation in multiwell tissue culture trays.

Ethanol can have direct effects in tissue culture and is often used as a solvent. Analysis of these effects will require a precise knowledge of the concentration over time in the particular system employed. We measured the disappearance rate of ethanol from multiwell culture trays (open system) containing single or multiple concentrations of ethanol over a 48-hr time period. The ethanol concentration was also measured at 72 hr in stoppered Erlenmeyer flasks (closed system). In multiwell culture trays, 1 and 0.3% ethanol (V/V) evaporated with a t1/2 of 6 to 12 hr. Media containing no ethanol but adjacent to wells with 1% ethanol accumulated ethanol with a peak of 0.2% at 12 hr. The evaporation of 0.3% ethanol was slower from wells adjacent to those containing 1% ethanol. At 72 hr, stoppered Erlenmeyer flasks, which originally contained 1% ethanol, still had a concentration of 0.85%. Since both evaporation and transfer can occur in an open system, it is necessary to specify precise conditions or measure concentrations in such systems. Alternatively, a closed system in which the concentration of ethanol is maintained can be employed.

Clinical Pharmacokinetics of Ethanol

The pharmacokinetics of ethanol after typical doses are described by a 1-compartment model with concentration-dependent elimination. The volume of distribution estimated from blood concentrations is about 37 L/70 kg. Protein binding of ethanol has not been reported. Elimination is principally by metabolism in the liver with small amounts excreted in the breath (0.7%), urine (0.3%), and sweat (0.1%). Metabolism occurs, principally by alcohol dehydrogenase, in the liver to acetaldehyde. Models of ethanol input and absorption are crucial to the description and understanding of the effects of ethanol dose on bioavailability. Little attention has been paid to evaluation of potential models. First-pass extraction of ethanol is predicted to be dependent on hepatic blood flow and ethanol absorption rate, with a typical extraction ratio of 0.2. The overall elimination process can be described by a capacity-limited model similar to the Michaelis-Menten model for enzyme kinetics. The maximum rate of elimination of ethanol (elimination capacity or Vmax is 8.5 g/h/70 kg. This would be equivalent to a blood ethanol disappearance rate of 230 mg/L/h if metabolism took place at its maximum rate. The elimination rate is half of the elimination capacity at a peripheral blood ethanol concentration (Km) of about 80 mg/L. Ethanol is readily detectable in expired air. The usual blood:expired air ratio is 2300:1 and breath clearance at rest is 0.16 L/h. The renal clearance of ethanol is 0.06 L/h and sweat clearance is 0.02 L/h. The use of a zero-order model of ethanol elimination has been widespread although the limitations of this model have been known for a long time. Much of the published work on ethanol pharmacokinetics must be regarded with suspicion because of this assumption.

Effect of muscimol on ethanol-induced central nervous system depression

In male Sprague-Dawley rats acute ethanol (1.0 and 2.0 g/kg) produced impairment of motor coordination and induced hypnosis (4.0 g/kg). Muscimol (1.25 mg/kg, IP) prior to ethanol administration enhanced motor impairment as measured by the aerial righting reflex. The rate of ethanol disappearance from the blood was unaltered by muscimol. Functional tolerance to the effect of ethanol on sleep time was produced by a 24 hr ethanol inhalation procedure. Animals tested 48 hr after ethanol inhalation exhibited a reduced sleep time from ethanol (4.0 g/kg). Muscimol (1.75 mg/kg) was administered along with ethanol 48 hr following 1 day of ethanol inhalation. Although the animals exhibited tolerance to ethanol-induced hypnosis, they did not menifest tolerance to the effect of muscimol.