Rate Of Ethanol Elimination Research Articles

Accelerated ethanol elimination via the lungs

Ethanol poisoning is endemic the world over. Morbidity and mortality depend on blood ethanol levels which in turn depend on the balance between its rates of absorption and clearance. Clearance of ethanol is mostly at a constant rate via enzymatic metabolism. We hypothesized that isocapnic hyperpnea (IH), previously shown to be effective in acceleration of clearance of vapour anesthetics and carbon monoxide, would also accelerate the clearance of ethanol. In this proof-of-concept pilot study, five healthy male subjects were brought to a mildly elevated blood ethanol concentration (~ 0.1%) and ethanol clearance monitored during normal ventilation and IH on different days. IH increased elimination rate of ethanol in proportion to blood levels, increasing the elimination rate more than three-fold. Increased veno-arterial ethanol concentration differences during IH verified the efficacy of ethanol clearance via the lung. These data indicate that IH is a nonpharmacologic means to accelerate the elimination of ethanol by superimposing first order elimination kinetics on underlying zero order liver metabolism. Such kinetics may prove useful in treating acute severe ethanol intoxication.

The Association between Ethanol Elimination Rate and Hangover Severity.

Assessments in blood and saliva suggests that the amount of ethanol present in the first hours after alcohol consumption and into the following morning is associated with hangover severity. The current analysis determines how ethanol elimination rate is related to hangover severity reported throughout the day. n = 8 subjects participated in two studies. The first was a naturalistic study comprising an evening of alcohol consumption. Hangover severity was assessed hourly from 10 a.m. to 4 p.m., using a 1-item hangover severity scale ranging from 0 (absent) to 10 (extreme). The second study comprised a highly controlled alcohol challenge to reach a breath alcohol concentration (BrAC) of 0.05%. Breathalyzer tests were conducted every 5 min until BrAC reached zero. The ethanol elimination rate, expressed in BrAC%/hour, was computed by dividing the peak BrAC (%) by the time to BrAC of zero (h). At 11:00, 13:00, and 14:00, there were significant negative partial correlations, controlling for estimated BrAC, between ethanol elimination rate and hangover severity. The findings suggest that drinkers with a faster ethanol elimination rate experience less severe hangovers. The observations should be confirmed in a larger sample of subjects who participate in a single study that assesses both hangover severity and ethanol elimination rate.

Activation of mitochondrial aldehyde dehydrogenase (ALDH2) by ALDA-1 reduces both the acquisition and maintenance of ethanol intake in rats: A dual mechanism?

A number of pre-clinical studies have shown that brain-generated acetaldehyde, the first metabolite of ethanol, exerts reinforcing effects that promote the acquisition of ethanol intake, while chronic intake maintenance appears to be mediated by alcohol-induced brain neuroinflammation/oxidative stress. Recently, it was described that N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (ALDA-1) activates aldehyde dehydrogenase-2 (ALDH2), enzyme that catalyzes the oxidation of ethanol-derived acetaldehyde to acetate. The aim of this study was to determine the effects of ALDA-1 on both the acquisition and the maintenance of alcohol intake in alcohol-preferring UChB rats. For ethanol acquisition studies, naïve UChB rats were treated with five daily doses of ALDA-1 (12.5, 25 or 50 mg/kg, i.p.) from one day before the start of ethanol exposure. For chronic intake studies, UChB rats exposed for 98 days to a free access to 10% ethanol and water were treated daily with ALDA-1 (12.5, 25 or 50 mg/kg, i.p.) for five days. The administration of ALDA-1 reduced by 72–90% (p < 0.001) the acquisition of ethanol consumption in naïve rats. At chronic ethanol consumption, ALDA-1 reduced ethanol intake by 61–82% (p < 0.001). ALDA-1 administration increased by 3- and 2.3-fold the activity of ALDH2 in brain and liver, respectively. ALDA-1 did not affect saccharin consumption, nor it modified the rate of ethanol elimination. The study shows that the activation of ALDH2 by ALDA-1 is effective for inhibiting both the acquisition and the maintenance of chronic ethanol intake by alcohol-preferring rats. Thus, the activation of brain ALDH2 may constitute a novel approach in the treatment of alcohol use disorders.

Modeling of Human Hepatic and Gastrointestinal Ethanol Metabolism with Kinetic-Mechanism-Based Full-Rate Equations of the Component Alcohol Dehydrogenase Isozymes and Allozymes.

Alcohol dehydrogenase (ADH) is the principal enzyme responsible for the metabolism of ethanol. Human ADH constitutes a complex family of isozymes and allozymes with striking variation in kinetic properties and tissue distribution. The liver and the gastrointestinal tract are the major sites for first-pass metabolism (FPM). The quantitative contributions of ADH isozymes and ethnically distinct allozymes to cellular ethanol metabolism remain poorly understood. To address this issue, kinetic mechanism and the steady-state full-rate equations for recombinant human class I ADH1A, ADH1B (including allozymes ADH1B1, ADH1B2, and ADH1B3), ADH1C (including allozymes ADH1C1 and ADH1C2), class II ADH2, and class IV ADH4 were determined by initial velocity, product inhibition, and dead-end inhibition experiments in 0.1 M sodium phosphate at pH 7.5 and 25 °C. Models of the hepatic and gastrointestinal metabolisms of ethanol were constructed by linear combination of the numerical full-rate equations of the component isozymes and allozymes in target organs. The organ simulations indicate that in homozygous ADH1B*1/*1 livers, a representative genotype among ethnically distinct populations due to high prevalence of the allele, major contributors at 1 to 10 mM ethanol are ADH1B1 (45% to 24%) and the ADH1C allozymes (54% to 40%). The simulated activities at 1 to 50 mM ethanol for the gastrointestinal tract (total mucosae of ADH1C*1/*1-ADH4 stomach and the ADH1C*1/*1-ADH2 duodenum and jejunum) account for 0.68%-0.76% of that for the ADH1B*1/*1-ADH1C*1/*1 liver, suggesting gastrointestinal tract plays a relatively minor role in the human FPM of ethanol. Based on the flow-limited sinusoidal perfusion model, the simulated hepatic Kmapp, Vmaxapp, and Ci at a 95% clearance of ethanol for ADH1B*1/*1-ADH1C*1/*1 livers are compatible to that documented in hepatic vein catheterization and pharmacokinetic studies with humans that controlled for the genotypes. The model simulations suggest that slightly higher or similar ethanol elimination rates for ADH1B*2/*2 and ADH1B*3/*3 individuals compared with those for ADH1B*1/*1 individuals may result from higher hepatocellular acetaldehyde.

Correlation of Genetic Polymorphism, Alcoholic Beverage Type and Ethanol Metabolism

To explore the effects of ADH1B and ALDH2 gene polymorphism and type of alcoholic beverage on ethanol metabolism, to provide data support for cases involving the interpretation of ethanol metabolism or back calculation of blood ethanol concentration in forensic practice. A total of 81 volunteers were selected. The genotypes of ADH1B, ADH1C and ALDH2 were obtained by a multiplex SNaPshot genotyping method. Each subject was administered with 1.0 g/kg of alcohol. About 1 mL venous blood was collected before and after the alcohol consumption at 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h and 8 h, respectively. The concentrations of ethanol and acetaldehyde in blood were determined by headspace gas chromatography. The peak times of blood ethanol concentration （Tmax）, the peak mass concentrations of ethanol （Cmax）, the area under curve （AUC） of ethanol （AUCethanol）, AUCacetaldehyde and ethanol elimination rates （β） were calculated. In order to eliminate the influence of ADH1C, the ADH1C*1/*1 carriers were grouped based on the genotype of ADH1B and ALDH2. The data of each group were evaluated by one-way analysis of variance and pairwise comparison tests were performed by least significant difference method. The gene interactions were evaluated by two-way analysis of variance. Each parameter of three kinds of alcoholic beverage （white wine, red wine and beer） among groups was analysed by variance analysis with randomized block design. There were no differences in the value of Tmax and Cmax between the groups with different ADH1B and ALDH2 genotype. The differences in the values of AUCethanol, β and AUCacetaldehyde among some groups carrying different ADH1B and ALDH2 genotype had statistical significance, while no significant difference was observed in these parameters when one individual taking same dose of different alcoholic beverage type. The ethanol metabolism is associated with the related gene polymorphism, which is barely affected by alcoholic beverage type.

Lack of effects of a “sobering” product, “Eezup!”, on the blood ethanol and congener alcohol concentration

IntroductionThe lifestyle product ‘Eezup!’ appeared on the German market and promised to normalize energy metabolism. Among vitamins (B1, B2, B6, C, E and zinc), rice protein and fructose the addition of alcohol dehydrogenase and catalase enzymes is a novel approach. The product was advertised as capable of boosting the rate of alcohol elimination. MethodsSeventeen subjects (11 men, 6 women, 19–58 years old), participated in a two-way crossover drinking study. Unfiltered wheat beer (4.4g% alcohol content) was drank within one hour to reach blood alcohol concentrations of 1‰ (1g/kg whole blood). On one day “Eezup!” was taken according to the manufacturer’s instructions before and after drinking which was substituted for a placebo on the second test day. Blood samples were taken during 9h and ethanol and congener alcohols were determined. A comparison of Cmax, tmax, area under the curve (AUC) for ethanol and congener alcohols, and the hourly elimination rate of ethanol (β60) was performed to investigate an effect of Eezup!. ResultsEthanol concentrations (Cmax) were in the range of 0,63–1,00‰ (median 0,85‰) and 0.62–1.22‰ (median 0.84‰) in the placebo and “Eezup!” condition, respectively, and not statistically different. Also tmax (1–2.5h) and AUCs did not differ. The ethanol elimination rates were 0.16‰/h (0.14–0.19‰/h) and 0.17‰/h (0.14–0.22 ‰/h) in the placebo and “Eezup!” condition without significant difference. The pharmacokinetic parameters of the congener alcohols (1-propanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butanol) as well as of methanol did also not differ. ConclusionsThe results of the present study failed to show any effect of the sobering product “Eezup!” on the amount of ethanol and congener alcohols absorbed (Cmax, tmax, AUC) and on the ethanol elimination rate (β60).

Role of Sumoylation in Alcohol Dehydrogenase 1 (ADH1) Stability and Activity in Alcoholic Liver Disease

BackgroundAlcohol abuse is a leading factor in mortality from liver disease and increases the risk for a wide range of adverse health effects. The liver, as the primary site of alcohol metabolism, is a major target of injury. The spectrum of Alcoholic Liver Diseases (ALD) includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol dehydrogenase 1 (ADH1) is an enzyme, member of the oxidoreductase family and it is a dimeric protein in the cytosol of cells. ADH1 plays a pivotal role in contributing to the increase in rate of ethanol elimination from the blood. As the first enzyme of the major oxidative pathway of alcohol metabolism, it converts ethanol into acetaldehyde. Acetaldehyde, a major toxic ethanol metabolite, is mutagenic and carcinogenic, playing an important role in the pathogenesis of alcoholic liver disease (ALD) inducing production of reactive oxygen species (ROS) and apoptosis. SUMOylation is a post‐translational modification that modulates multiple cellular processes such as signal transduction, stress responses, cellular trafficking, protein‐protein interactions, protein‐DNA interactions, and transcriptional activity. Sumoylation is oxidative stress inducible. There are four distinct types of SUMO, small ubiquitin‐like modifier, proteins in humans (SUMO‐1, −2, 3‐ and −4). SUMOylation is often increased under oxidative stress. We recently reported that ubiquitin conjugating enzyme 9 (Ubc9), the sole E2 enzyme of SUMOylation, is induced in intragastric ethanol‐infusion (EI) treated mice. Our aim was to examine whether the dysregulated sumoylation could influence the ethanol‐induced ADH1 function in both ALD and HCC elucidating the molecular mechanism(s).MethodsMass Spectrometry by SUMO binding columns was performed to purify sumoylated proteins form total livers of Binge ethanol fed mouse model. Primary mouse hepatocytes and HepG2 cells (HCC cell line) were used to perform in vitro experiments. Protein and mRNA levels were measured using Western Blotting and RT‐PCR, respectively. Tryglicerides production was examined by Nile red staining.ResultsWe found that ADH1 is sumoylated in binge mice livers analyzing the peptide‐sequencing data from sample purified by SUMO immunoaffinity columns. In vitro experiments showed ethanol treatment increased ADH1 protein and mRNA levels in primary mouse hepatocytes and HepG2 cells. Sumoylation controls ADH1 expression and protein stability in ethanol treatment cellular model providing a protein stability in co‐treatment with ethanol. In addition, we found Ubc9 is required for ethanol‐induced triglycerides accumulation.ConclusionsWe report for the first time that ethanol‐mediated sumoylation increased ADH1 protein level in livers of binge mice and that ethanol feeding modulates the sumoylation status of the key proteins in alcoholic liver disease.. Sumoylation could play an important role in modulating ADH1 enzymatic activity by its expression and protein stability control. This novel finding thereby opens a new area of investigation examining the importance of ADH1 sumoylation in alcoholic liver disease and in HCC maybe suggesting its potential role in the therapeutic approch.Support or Funding InformationSupported by NIH grant 5 K01 AA022372‐04(Maria Lauda Tomasi)

Ethanol elimination rates at low concentrations based on two consecutive blood samples

IntroductionFor ethanol, the elimination curve change from apparent zero to apparent first order kinetics at low blood alcohol concentrations (BACs). This is less studied than elimination at higher BACs, and knowledge about this low BAC elimination is especially missing in drunk drivers representing a population with a high frequency of heavy drinkers with increased rate of ethanol metabolism. The aim of this study was to investigate the point at which elimination rates turns from zero to first order kinetics and the exact elimination rates at the very low BAC intervals in drunk drivers. MethodsTwo consecutively collected samples from suspected drunk drivers were used. All samples were analyzed by two headspace gas chromatography flame ionization detector methods (limit of quantification=0.04g/kg). The elimination rates at BACs below 0.25g/kg (study group, n=175) was studied in detail, and compared to the elimination rates in a moderate BAC reference group (n=789) as well as a high BAC reference group (n=4435). ResultsThere were no differences in age, gender and drivings occurring during night-time between the study group and the reference groups. The mean elimination rates were stable at 0.18–0.19g/kg/h from a BAC of 4.0g/kg and until BAC in the first blood sample fell below 0.19g/kg. At BACs below 0.19g/kg, the mean elimination rate gradually declined from 0.163g/kg/h to the lowest elimination rate of 0.083g/kg/h. There was no relation between the concentration of ethanol and elimination rate at BACs above 0.19g/kg (Pearson's r=0.035, p=0.3), but there was a strong relation between concentration of ethanol and elimination rate at BACs below 0.19g/kg (Pearson's r=0.56, p<0.001). ConclusionIn conclusion, the present study showed that in a population of drunk drivers, the shift from zero order to first order kinetics occurs when BAC falls below 0.19g/kg. Below this points, the present study indicate that drunk drivers show elimination rates comparable to the normal population. These results could assist in back-calculations in cases of drunk driving involving low BACs.

Elimination Kinetics of Ethanol in a 5-Week-Old Infant and a Literature Review of Infant Ethanol Pharmacokinetics

Primary ethanol metabolism occurs through alcohol dehydrogenase, but minor metabolic pathways such as the P450 enzymes CYP2E1 and CYP1A2 and the enzyme catalase exist. These enzymes have distinct developmental stages. Elimination kinetics of ethanol in the infant is limited. We report the elimination kinetics of ethanol in a 5-week-old African-American male who had a serum ethanol level of 270 mg/dL on admission. A previously healthy 5-week-old African-American male was brought to the ED with a decreased level of consciousness. His initial blood ethanol level was 270 mg/dL. Serial blood ethanol levels were obtained. The elimination rate of ethanol was calculated to be in a range from 17.1 to 21.2 mg/dL/hr and appeared to follow zero-order elimination kinetics with a R 2 = 0.9787. Elimination kinetics for ethanol in the young infant has been reported in only four previously published reports. After reviewing these reports, there appears to be variability in the elimination rates of ethanol in infants. Very young infants may not eliminate ethanol as quickly as previously described. Given that there are different stages of enzyme development in children, caution should be used when generalizing the elimination kinetics in young infants and children.

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.

Betaine feeding prevents the blood alcohol cycle in rats fed alcohol continuously for 1 month using the rat intragastric tube feeding model

Background Blood alcohol levels (BAL) cycle up and down over a 7–8 day period when ethanol is fed continuously for one month in the intragastric tube feeding rat model (ITFRM) of alcoholic liver disease. The cycling phenomenon is due to an alternating increase and decrease in the metabolic rate. Recently, we found that S-adenosyl-methionine (SAMe) fed with alcohol prevented the BAL cycle. Method Using the ITFRM we fed rats betaine (2 g/kg/day) with ethanol for 1 month and recorded the daily 24 h urine ethanol level (UAL) to measure the BAL cycle. UAL is equivalent to BAL because of the constant ethanol infusion. Liver histology, steatosis and BAL were measured terminally after 1 month of treatment. Microarray analysis was done on the mRNA extracted from the liver to determine the effects of betaine and alcohol on changes in gene expression. Results Betaine fed with ethanol completely prevented the BAL cycle similar to SAMe. Betaine also significantly reduced the BAL compared to ethanol fed rats without betaine. This was also observed when SAMe was fed with ethanol. The mechanism involved in both cases is that SAMe is required for the conversion of epinephrine from norepinephrine by phenylethanolamine methyltransferase (PNMT). Epinephrine is 5 to 10 fold more potent than norepinephrine in increasing the metabolic rate. The increase in the metabolic rate generates NAD, permitting ADH to increase the oxidation of alcohol. NAD is the rate limiting factor in oxidation of alcohol by alcohol dehydrogenase (ADH). This explains how SAMe and betaine prevented the cycle. Microarray analysis showed that betaine feeding prevented the up regulation of a large number of genes including TLR2/4, Il-1b, Jax3, Sirt3, Fas, Ifngr1, Tgfgr2, Tnfrsf21, Lbp and Stat 3 which could explain how betaine prevented fatty liver. Conclusion Betaine feeding lowers the BAL and prevents the BAL cycle by increasing the metabolic rate. This increases the rate of ethanol elimination by generating NAD.

S-adenosylmethionine decreases the peak blood alcohol levels 3 h after an acute bolus of ethanol by inducing alcohol metabolizing enzymes in the liver

Introduction An alcohol bolus causes the blood alcohol level (BAL) to peak at 1–2 h post ingestion. The ethanol elimination rate is regulated by alcohol metabolizing enzymes, primarily alcohol dehydrogenase (ADH1), acetaldehyde dehydrogenase (ALDH), and cytochrome P450 (CYP2E1). Recently, S-adenosylmethionine (SAMe) was found to reduce acute BALs 3 h after an alcohol bolus. The question, then, was: what is the mechanism involved in this reduction of BAL by feeding SAMe? To answer this question, we investigated the changes in ethanol metabolizing enzymes and the epigenetic changes that regulate the expression of these enzymes during acute binge drinking and chronic drinking. Methods Rats were fed a bolus of ethanol with or without SAMe, and were sacrificed at 3 h or 12 h after the bolus. Results RT-PCR and Western blot analyses showed that SAMe significantly induced ADH1 levels in the 3 h liver samples. However, SAMe did not affect the changes in ADH1 protein levels 12 h post bolus. Since SAMe is a methyl donor, it was postulated that the ADH1 gene expression up regulation at 3 h was due to a histone modification induced by methylation from methyl transferases. Dimethylated histone 3 lysine 4 (H3K4me2), a modification responsible for gene expression activation, was found to be significantly increased by SAMe at 3 h post bolus. Conclusion These results correlated with the low BAL found at 3 h post bolus, and support the concept that SAMe increased the gene expression to increase the elimination rate of ethanol in binge drinking by increasing H3K4me2.

Letter to the Editor in Regard to Baek, Lee, and Kwon (2010): “Influence of Dissolved Oxygen Concentration on the Pharmacokinetics of Alcohol in Humans”

Alcoholism: Clinical and Experimental ResearchVolume 34, Issue 10 p. 1671-1672 Letter to the Editor in Regard to Baek, Lee, and Kwon (2010): “Influence of Dissolved Oxygen Concentration on the Pharmacokinetics of Alcohol in Humans” Does Oxygenated Alcohol Reduce Hangover? Dirk W. Lachenmeier, Dirk W. Lachenmeier From the Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe (DWL), Karlsruhe, Germany; Centre for Addiction and Mental Health (CAMH) (JR), Toronto, Ontario, Canada.Search for more papers by this authorJürgen Rehm, Jürgen Rehm From the Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe (DWL), Karlsruhe, Germany; Centre for Addiction and Mental Health (CAMH) (JR), Toronto, Ontario, Canada.Search for more papers by this author Dirk W. Lachenmeier, Dirk W. Lachenmeier From the Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe (DWL), Karlsruhe, Germany; Centre for Addiction and Mental Health (CAMH) (JR), Toronto, Ontario, Canada.Search for more papers by this authorJürgen Rehm, Jürgen Rehm From the Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe (DWL), Karlsruhe, Germany; Centre for Addiction and Mental Health (CAMH) (JR), Toronto, Ontario, Canada.Search for more papers by this author First published: 01 July 2010 https://doi.org/10.1111/j.1530-0277.2010.01253.xCitations: 2 Reprint requests: Dirk W. Lachenmeier, Dr. rer.nat., Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weißenburger Str. 3, D-76187 Karlsruhe, Germany; Tel.: +49-721-926-5434; Fax: +49-721-926-5539; E-mail: Lachenmeier@web.de Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume34, Issue10October 2010Pages 1671-1672 RelatedInformation

The influence of the luteal and follicular phases on major pharmacokinetic parameters of blood and breath alcohol kinetics in women

Drink tests involving 14 women were carried out to determine the effects of the menstrual cycle phases on the pharmacokinetics of ethanol. One experiment was carried out in the follicular phase of the cycle and another in the luteal phase, with the estradiol, progesterone, and testosterone levels being determined in both cases. The target concentration was a final blood alcohol concentration (BAC) of approximately 0.08 g%. After drinking was completed, concurrent BAC and breath alcohol concentration (BrAC) measurements were carried out at intervals of 10–20 min. The ethanol elimination rate was determined by calculating a linear function in the part of the slope that was clearly linear. In addition, the c 0 and Widmark factors r were calculated. In 10 of the volunteers, who had a normal increase in progesterone in the luteal phase, the average hourly elimination rate ß 60 in the follicular phase amounted to 0.0194 ± 0.0020 g%/h (BAC) and 0.0975 ± 0.0068 mg/L/h (BrAC), and in the luteal phase to 0.0193 ± 0.0031 g%/h (BAC) and 0.1026 ± 0.0101 mg/L/h (BrAC). There was no significant difference. Other pharmacokinetic parameters ( c 0 concentrations, Widmark factors r, distribution volumes, maximal BAC, mean absorption rate, time until the peak concentrations were reached) also revealed no significant differences between the blood and breath alcohol levels of the luteal and follicular phases. In addition, no significant correlations were observed between the absolute progesterone level and the respective elimination rates ß 60.

SIAM‐Like Phenomenon Caused by Low Doses of Alcohol

Swift increase in alcohol metabolism (SIAM) is usually evoked by a large dose of ethanol, which is often demonstrated by an abrupt increase in oxygen uptake. SIAM was induced by low doses of ethanol and evaluated by pharmacokinetic analyses of ethanol and its metabolites. Rabbits were initially administered 1.0 g/kg of ethanol solution and the same dose was given to the bolus group 6 hours after the first injection. The infusion group was administered 0.25 g/kg/h of ethanol 2 hours after the first injection. Blood concentrations of ethanol, acetaldehyde, and acetate were then determined and comparisons were made using pharmacokinetic parameters. A significantly higher ethanol elimination rate was observed after re-administration of ethanol to the bolus group. Other pharmacokinetic parameters were unaffected. The concentration at steady state (Css) for the infusion group was stable. A significantly higher level of mean residence time (MRT) in blood acetaldehyde was observed for the bolus group, whereas no MRT changes were observed for the infusion group. A significantly higher level of blood acetate Css was observed after re-administration of ethanol to the bolus group, following the changes in area under concentration and MRT. No Css changes were observed for the infusion group. The Css of acetate at stage 2 was significantly higher for the bolus group, compared to the infusion group. Low doses of ethanol enhanced alcohol metabolism in rabbits, according to a pharmacokinetic analysis of circulating ethanol concentrations. Simultaneous analyses of its metabolites followed the kinetic of ethanol.

Estimating the degree of ethanol intoxication from analysis of cerebro-cranial hematomas

314 cases of combined cerebro-cranial trauma and posttraumatic intracranial hematomas were identified of which ethanol was detected in 114 hematomas. The other investigative group was 103 hospitalized patients who had hematomas evacuated during neurosurgical procedures. In 62 of these cases ethanol was detected. Blood and urine samples were also collected and the alcohol concentration was determined in all specimens by GC and ADH. The ethanol elimination rate for autopsy and operative intracranial hematomas was approximately 0.07–0.08‰/h(±0.034‰/h). The elimination rate of ethanol from blood (β 60) was about two or three times greater as that from hematomas. Because of the different water content of intracranial hematomas from blood, it was necessary to adjust the ethanol concentration for water content. On the basis of the corrected ethanol concentrations and the elimination rates for both tissues it was possible to estimate the ethanol concentration at the time of injury. Intracranial hematomas are tissues of possible value in the determination of alcohol intoxication especially in alcoholism. Ethanol can be found in hematomas even after 72 h from head injury.

PRECLINICAL STUDY: Circadian regulation of central ethanol sensitivity by the mPer2 gene

The effect of alcohol is known to vary with the time of the day. Although initially it was suggested that this phenomenon may be due to diurnal differences in ethanol metabolism, more recent studies were contradicting. In the present study, we therefore first set out in assessing the diurnal variations in ethanol sensitivity in mice analysing, concurrently, ethanol elimination rates. Ethanol-induced (3.5 g/kg; intraperitoneal) loss of righting reflex (LORR) duration was thus determined at several Zeitgeber time (ZT) points (ZT5, 11, 17 and 23) in C57BL/6N mice. In parallel, the corresponding ethanol elimination rates were also assessed. The results display the existence of a distinct diurnal rhythm in LORR duration peaking at ZT11, whereas no differences could be observed regarding the elimination rates of alcohol. Successively, we checked the involvement of the clock genes mPer1 and mPer2 in conveying this rhythm in sensitivity, testing LORR and hypothermia at the peak and trough previously observed (ZT5 and ZT11). Per1(Brdm1) mice demonstrate a similar diurnal pattern as control mice, with enhanced LORR durations at ZT11. In contrast, Per2(Brdm1) mice did not exhibit a temporal variation to the depressant effects of ethanol with respect to LORR, revealing a constant high sensitivity to ethanol. The present study reveals a central role of the mPer2 gene in inhibiting alcohol sensitivity at the beginning of the inactive phase.

Estimated Blood Alcohol Concentrations for Child and Adolescent Drinking and Their Implications for Screening Instruments

Blood alcohol concentrations (BACs) in children after consumption of different numbers of standard drinks of alcohol have not been estimated previously. The goal was to determine the number of drinks at each age that led to a BAC of > or =80 mg/dL, the National Institute on Alcohol Abuse and Alcoholism criterion for binge drinking. The updated Widmark equation to estimate BAC was modified to take account of the differing body composition (total body water) and accelerated rates of ethanol elimination of children. The modified formula was used with 1999-2002 National Health and Nutrition Examination Survey data to estimate BACs for >4700 children and adolescents from 9 through 17 years of age, for intake levels of 1 to 5 standard drinks. The estimated BACs for children after consumption of just 3 standard drinks within a 2-hour period were between 80 and 139 mg/dL for boys 9 to 13 years of age and for girls 9 to 17 years of age, indicating substantial potential alcohol impairment. With 5 drinks within 2 hours (the level used to define binge drinking among college students), children 9 to 13 years of age were estimated to have BACs 2 to 3 times the adult legal limit for intoxication of 80 mg/dL. Binge drinking should be defined as > or =3 drinks for 9- to 13-year-old children, as > or =4 drinks for boys and > or =3 drinks for girls 14 or 15 years of age, and as > or =5 drinks for boys and > or =3 drinks for girls 16 or 17 years of age.

A regression model applied to gender-specific ethanol elimination rates from blood and breath measurements in non-alcoholics

As elimination rates for alcohol are suggested to be gender specific, a novel regression model has been applied to estimate these rates for both men and women using experimentally measured data from 81 female and 96 male volunteers described in previous papers. Breath alcohol measurements were done with the Alcotest 7110 Evidential device and were coupled with concomitant sampling of venous blood. Statistical analyses involved use of a mixed linear model for blood alcohol concentration (BAC) and breath alcohol concentration (BrAC), respectively. The model takes regression lines for each test subject into account with an individual starting value (2 h after the end of drinking) and with an individual alcohol elimination rate per hour (coincidental effects). Further, the data was modeled so that an average alcohol elimination rate per hour could be estimated separately for both genders (constant effects). This enables us to methodically correctly estimate the back calculation. The elimination rates beta (60), which can be used for minimum and maximum back calculations for the BAC, were 0.115 g/kg/h and 0.260 g/kg/h, respectively, for women and 0.096 g/kg/h and 0.241 g/kg/h, respectively, for men. These figures widely deviate from gender-unspecific values commonly used in Germany (0.1 and 0.2 g/kg/h, respectively). The corresponding values for the BrAC were 0.061 mg/l/h and 0.124 mg/l/h for women and 0.049 mg/l/h and 0.112 mg/l/h for men. The probability of an over- or underestimation of the abovementioned extreme values is 0.3% in each case.

Effect of metoprolol on the elimination kinetics of ethanol

Eight healthy probands received 1.0 to 1.3 g ethanol per kg body weight within a period of 30 minutes. The average hourly elimination rate of ethanol during the postresorptive phase was found to be 0.18 g/l. No significant increase in the elimination rate was seen either after administration of 200 mg metoprolol per day in slow release form for a period of one week, or after a single dose of 200 mg metoprolol in standard formulation taken at the beginning of ethanol ingestion. On the other hand, long-term administration of metoprolol resulted in a steeper rise and a delayed decrease of blood alcohol concentration. Simultaneous intake of metoprolol and of alcohol in high dosage should be avoided.