Alcohol Pharmacokinetics Research Articles

The pharmacokinetics of alcohol for essential tremor

The pharmacokinetics of alcohol for essential tremor

Severe alcohol‐induced neuronal deficits in the hippocampus and neocortex of neonatal mice genetically deficient for neuronal nitric oxide synthase (nNOS)

Alcohol can severely damage the developing brain, and neuronal loss is a critical component of this injury. Thus, identification of molecular factors that ameliorate alcohol-induced neuronal loss is of great importance. Previous in vitro work has demonstrated that nitric oxide (NO) protects neurons against alcohol toxicity. We tested the hypothesis that neonatal mice carrying a null mutation for neuronal nitric oxide synthase (nNOS), the enzyme that synthesizes NO in neurons, have an increased vulnerability to alcohol-induced neuronal loss in the neocortex and hippocampus. Wildtype mice and nNOS-/- mice received ethanol (0.0, 2.2, 3.3, or 4.4 g/kg) daily over postnatal days (P) 4-9 and were sacrificed on P10. The number of hippocampal CA1 and CA3 pyramidal cells, dentate gyrus granule cells, and neocortical neurons were determined using stereological methods. Alcohol pharmacokinetics did not differ between wildtype and nNOS-/- strains. Alcohol induced dose-dependent reductions in all four neuronal populations, and the losses were substantially more severe in the nNOS-/- mice than in wildtype. Furthermore, the threshold dose of alcohol to induce cell death was lower in the nNOS-/- mice than in the wildtype mice for all neuronal populations. While nNOS deficiency worsened alcohol-induced neuronal losses, the magnitude of this exacerbation varied among brain regions and depended on alcohol dose. These results demonstrate that nNOS deficiency decreases the ability of developing neurons in vivo to survive the toxic effects of alcohol and strengthen the hypothesis that NO exerts a neuroprotective effect against alcohol toxicity in the developing brain.

Standardization of Alcohol Calculations in Research

Nonstandardized reporting of alcohol consumption, definitions of what constitutes a standard drink, and incomplete dosing or estimates of intoxication are common problems in many areas of alcohol research. To enhance communication among scientists and to make interpretation of results more accurate and meaningful, researchers need to apply systematically current scientific principles in calculating drinks, doses, and alcohol concentrations. Basic formulas are compiled and explained to assist alcohol researchers and standardize the reporting and interpretation of alcohol data. Basic alcohol calculations are reviewed, and 20 mathematical calculations in alcohol pharmacokinetics and pharmacology are derived. Examples of how each calculation works are presented. The formulas presented enable researchers to calculate accurately and systematically the amount of alcohol in any beverage and estimate the blood alcohol concentration in a range of subjects with individual characteristics and drinking patterns. Accurate estimates of alcohol use and intoxication are important in many areas of research. Applying standards to the way alcohol is measured and interpreted enables better communication, more accurate analyses, and, in some cases, may impact the interpretation of results. Regardless of the field of study, alcohol researchers are encouraged to and can apply uniform standards in measuring alcohol consumption and estimating the effects of alcohol using the scientific methodologies described.

Do alcohol pharmacokinetics in women vary due to the menstrual cycle?

Many authors in the alcohol field believe that the physiological responsiveness of women to alcohol varies during the menstrual cycle, due to changes in levels of sex steroid hormones. Statements about this issue are very contradictory, however. The aim of this review was to decide what valid evidence was available on this issue. Three criteria were set to assess the validity of the reviewed studies: (1) was a within-subjects design used with normally cycling subjects, (2) were the time points selected for testing characterized by significant variations in sex steroid activity, and (3) was it verified whether ovulation occurred in the subjects by measuring levels of sex steroids? Two of the 11 studies we examined met these criteria. These studies, emanating from the same laboratory, found that alcohol elimination increased, by about 14%, during the luteal phase compared to other phases of the cycle. The results were discussed in relation to other research regarding effects of sex steroids on alcohol metabolism. It is concluded that there is no evidence that menstrual cycle causes significant instability in alcohol pharmacokinetics in women.

Alcohol levels in Chinese lactating mothers after consumption of alcoholic diet during postpartum “doing-the-month” ritual

This study examined the effects of exposure to ethanol through cultural practices by lactating mothers. Specifically, the pharmacokinetics of alcohol in Chinese lactating mothers was investigated after they consumed chicken soup flavored with sesame oil and rice wine (CSSR), a typically prescribed diet during the postpartum “doing-the-month” period. Experimental findings were employed to estimate the potential ethanol dose to neonates and determine associated health risks. Twenty-three lactating mothers were examined. Informed consent was obtained from each subject. The target alcohol dosage was 0.3 g/kg. Milk and blood samples were collected at fixed time intervals from each subject following exposure to CSSR, and alcohol levels were determined. Acute health risks to infants were estimated by comparing the potential infant dosage to an established criterion dose. Blood alcohol level peaked at 20 min after exposure to CSSR and decreased almost linearly thereafter. Alcohol in milk reached a plateau roughly at 20–40 min after exposure to CSSR and then decreased. Alcohol pharmacokinetics among subjects varied widely. The coefficients of variation in subject alcohol concentrations were 16.5–46.2% (mean, 30.0%) for blood and 32.8–57.6% (mean, 44.4%) for milk. Mean maximal alcohol concentration in blood (30.2 ± 5.0 mg/dl) was achieved at 23.5 ± 7.6 min and in milk (31.6 ± 10.3 mg/dl) at 31.7 ± 12.7 min. Potential infant doses were 3.0–58.8 mg (mean, 13.4 mg), and the predicted time required for milk alcohol level to return to zero level was 175 min. The acute health risks for infants exposed to alcohol through their mothers' milk under the current exposure scenario are low (hazard index < 0.2). Nursing infants at least 3 h after ingesting a diet containing alcohol would further reduce potential health risks.

Individual differences in the kinetics of alcohol absorption and elimination : A human study.

The individual differences in alcohol pharmacokinetics were studied using the one-compartment model with first-order absorption and zero-order elimination kinetics in humans. The blood alcohol concentrations (BACs) were simulated by obtained parameters, absorption rate constant (ka), and climination rate constant (β). The 81 healthy young Japanese volunteers, who had been divided into those without alcohol-induced facial flushing (nonflushers) and those with facial flushing (flushers) according to alcohol patch test results and a questionnaire beforehand, ingested 0.50 g/kg ethanol within 1 minute. Breath alcohol concentrations (BrACs) were measured during absorption and during the elimination period. BACs were obtained based on BrACs. Fifteen percent of subjects exhibited low BAC profile (below 0.4 mg/mL) (first-pass effect [FPE] group), although the majority showed normal BAC profile (normal group). The ka was approximately 5 to 8 (h(-1)) in the normal group without significant difference between nonflushers and flushers, whereas that in the FPE group was significantly smaller than in the normal group. For the normal group, peak BACs were well simulated by the one-compartment model with first-order absorption and zero-order elimination kinetics. A considerable portion of subjects exhibited FPE. Absorption of alcohol from the intestine plays an important role in alcohol pharmacokinetics in humans.

A pilot study of alcohol exposure and pharmacokinetics in women with or without children with fetal alcohol syndrome.

To determine the alcohol exposure and pharmacokinetics of alcohol in a group of women who had given birth to children with FAS, compared with women who had not given birth to FAS children. 10 women who had given birth to FAS children (FAS mothers) and 20 Controls were studied to determine how they metabolize alcohol in a single limited-access quasi-experimental session of voluntary consumption of alcohol. They had free choice in the consumption of any amount of their favourite beverage for approximately 2.5 h, but their drinking was terminated if the breath alcohol concentrations (BrAC) exceeded 150 mg%. BrACs was measured during ethanol consumption and for several hours after, for estimation of alcohol exposure and pharmacokinetics. FAS mothers consumed significantly larger amounts of alcohol, and achieved significantly higher peak BrAC levels than Controls. The rate of decline of alcohol from the circulation (beta-60) showed a 2-fold variation across subjects but there was no significant difference between the two groups. This study did not show any difference in alcohol pharmacokinetics in free-choice drinking by non-pregnant women, who either have given or have never given birth to FAS children. However, mothers of FAS children tend to consume more alcohol per session. Future studies in larger samples will be needed to confirm these findings and to examine drinking patterns and other factors that may increase the risk of FAS in children of women who drink alcohol during pregnancy.

Gender differences in alcohol metabolism. Physiological responses to ethanol.

A gender difference in alcohol pharmacokinetics has been suggested to explain why women are more vulnerable to ethanol's toxic effects. The results of animal experiments suggest that females exhibit higher alcohol metabolic rates than males as a result of hormonal differences. Experimental results examining gender differences in human alcohol metabolism have been inconsistent; the diversity of experimental protocols and variety of pharmacokinetic parameters reported have made comparisons of these studies very difficult. Variability in alcohol metabolic rate between individuals of the same sex is often significant, preventing an assessment of gender differences in some studies. This chapter attempts to summarize the findings of studies from the last decade that examined the role of gender and sex hormone differences on ethanol metabolism in men and women. The role of body composition, genetic factors, gastric and hepatic alcohol dehydrogenase, and gastric absorption in creating gender differences in alcohol metabolism is discussed. Suggestions are offered that may result in better cross-study comparisons and more consistent experimental results.

Pharmacokinetics of ethanol: a review of the methodology

This paper reviews current concepts on tools for studying the pharmacokinetics of alcohol. It has been known that ethanol metabolism occurs mainly in the liver via alcohol dehydrogenase and an accessory microsomal pathway. The contribution of each pathway has been examined by administration of metabolic inhibitors. The role of gastric alcohol dehydrogenase in the first-pass effects of ethanol has been speculative and may be relatively low. Some pharmacokinetic approaches with mathematical models have elucidated the role of gastric alcohol dehydorgenase, hepatic alcohol dehydrogenase and cytochrome P450 2E1 in ethanol elimination. The scale-up of ethanol elimination kinetics has enabled extrapolation from animal models to human kinetics. The clarification of the pharmacokinetics of ethanol is very important for estimating the effects of ethanol on biological events.

Variation in Alcohol Pharmacokinetics as a Risk Factor for Alcohol Dependence

The significant association between alcohol dehydrogenase (ADH)-2 genotype and alcohol-dependence risk, demonstrated in both Asian and non-Asian populations, suggests a link between the metabolism of alcohol (ethanol) and individual differences in susceptibility to dependence. We tested this hypothesis by following up on subjects who took part in the Alcohol Challenge Twin Study conducted in 1979-1981 and comparing the blood and breath alcohol results in that study between subjects who subsequently did or did not meet diagnostic criteria for lifetime alcohol dependence in 1992-1993. Subjects who met DSM-III-R criteria for lifetime alcohol dependence at follow-up had higher blood and breath alcohol values after alcohol challenge than never-dependent subjects. Multivariate analysis showed independent effects of susceptibility to alcohol dependence and smoking status on blood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood or breath alcohol concentrations in the highest quartile than in the lowest quartile. In view of this association and the known genetic influences on both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than the known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.

Variation in Alcohol Pharmacokinetics as a Risk Factor for Alcohol Dependence

Background: The significant association between alcohol dehydrogenase (ADH)-2 genotype and alcohol-dependence risk, demonstrated in both Asian and non-Asian populations, suggests a link between the metabolism of alcohol (ethanol) and individual differences in susceptibility to dependence. Methods: We tested this hypothesis by following up on subjects who took part in the Alcohol Challenge Twin Study conducted in 1979–1981 and comparing the blood and breath alcohol results in that study between subjects who subsequently did or did not meet diagnostic criteria for lifetime alcohol dependence in 1992–1993. Results: Subjects who met DSM-III-R criteria for lifetime alcohol dependence at follow-up had higher blood and breath alcohol values after alcohol challenge than never-dependent subjects. Multivariate analysis showed independent effects of susceptibility to alcohol dependence and smoking status on blood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood or breath alcohol concentrations in the highest quartile than in the lowest quartile. Conclusions: In view of this association and the known genetic influences on both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than the known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.

Gender Differences in Pharmacokinetics of Alcohol

Gender Differences in Pharmacokinetics of Alcohol

Gender Differences in Pharmacokinetics of Alcohol

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

Research advances in ethanol metabolism

The pharmacokinetics of alcohol determines the time course of alcohol concentration in blood after the ingestion of an alcoholic beverage and the degree of exposure of organs to its effects. The interplay between the kinetics of absorption, distribution and elimination is thus important in determining the pharmacodynamic responses to alcohol. There is a large degree of variability in alcohol absorption, distribution and metabolism, as a result of both genetic and environmental factors. The between-individual variation in alcohol metabolic rates is, in part due to allelic variants of the genes encoding the alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). This review summarizes recent developments in the investigation of the following influences on alcohol elimination rate: gender, body composition and lean body mass, liver volume, food and food composition, ethnicity, and genetic polymorphisms in alcohol metabolizing enzymes as well as in the promoter regions of the genes for these enzymes. Evaluation of the factors regulating the rates of alcohol and acetaldehyde metabolism, both genetic and environmental, will help not only to explain the risk for development of alcoholism, but also the risk for development of alcohol-related organ damage and developmental problems.

Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination

Alcoholism: Clinical and Experimental ResearchVolume 24, Issue 4 p. 424-425 Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination Susan E. Shoaf, Corresponding Author Susan E. Shoaf Unit of Phamacokinetic Studies, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.Reprint requests: Susan Shoaf, M.D., OTSUKA American Pharmaceuticals, 2440 Research Blvd., Rockville, MD 20850; Fax: 301-721-7127; E-mail: susans@mocr.oapi.comSearch for more papers by this author Susan E. Shoaf, Corresponding Author Susan E. Shoaf Unit of Phamacokinetic Studies, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.Reprint requests: Susan Shoaf, M.D., OTSUKA American Pharmaceuticals, 2440 Research Blvd., Rockville, MD 20850; Fax: 301-721-7127; E-mail: susans@mocr.oapi.comSearch for more papers by this author First published: 11 April 2006 https://doi.org/10.1111/j.1530-0277.2000.tb02007.xCitations: 5AboutPDF 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 Volume24, Issue4April 2000Pages 424-425 RelatedInformation

Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination

Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination

Alcohol and drug intoxication

This is a textbook on the medical and legal aspects of alcohol and drug intoxication. It includes chapters on: (1) the chemistry of alcohol; (2) pharmacodynamics of alcohol; (3) pharmacokinetics of alcohol; (4) alcohol measurement in the body; (5) breath test physiology; (6) breath test technology; (7) empirical blood alcohol estimation; (8) toxic action of alcohol; (9) alcohol and driving; (10) pathology of alcohol; and (11) drugs, drinking and driving. Chapter 9 includes information on major studies into crash involved drinking drivers: the Holcombe Study; Toronto Studies; Coldwell Study; and the most extensive Grand Rapids Study (Borkenstein, 1964). In Chapter 11 information on hazardous drugs including cocaine, LSD, cannabis, amphetamines, and the interaction between drugs and alcohol.

Effects of isoflavones on alcohol pharmacokinetics and alcohol-drinking behavior in rats

Puerarin, daidzin, and daidzein are 3 major isoflavonoid compounds isolated from Pueraria lobata, an edible vine used widely in China for various medicinal purposes. We studied the antiinebriation and the antidipsotropic effects of these antioxidants in rats. Daidzin and daidzein shortened alcohol-induced sleep time (loss of righting reflex) in rats that were given ethanol intragastrically but not in those given ethanol intraperitoneally. When daidzin was given to animals intragastrically with the ethanol solution, the blood alcohol concentration (BAC) was found to peak later and be lower than in control rats that were given only the ethanol solution. BACs also receded more slowly if daidzin was fed to the animals. None of the 3 isoflavonoid compounds administered orally affected liver alcohol dehydrogenase or aldehyde dehydrogenase activities, as was reported for intraperitoneal administration. Further experiments indicated that the suppression of the BAC by daidzin was due mainly to delay of stomach emptying. All 3 compounds suppressed voluntary alcohol consumption in alcohol-preferring rats. The decrease in alcohol consumption was accompanied by an increase in water intake, so that the total volume of liquid consumed daily remained unchanged. Daily food consumption and body weight gain were not affected. Alcohol preference returned to baseline levels after the isoflavonoids were discontinued. We postulate that the suppression of alcohol reinforcement produced by these compounds is mediated centrally in the brain reward pathway.

Increased impulsivity after injected alcohol predicts later alcohol consumption in rats: evidence for "loss-of-control drinking" and marked individual differences.

A delay-of-reward paradigm was used to assess impulsivity in rats. Previous research with this paradigm has found that normally occurring impulsivity scores predict magnitude of voluntary alcohol intake. The authors' primary findings were (a) injected alcohol produced a dose-dependent increase in impulsivity, (b) varying the intervals between alcohol and testing yielded orderly effects, (c) there were extreme individual differences in impulsive reactivity to alcohol, (d) these individual differences did not reflect differences in alcohol pharmacokinetics, (e) subject selection procedures ensured that differences in impulsive reactivity to alcohol were independent of significant variations in baseline impulsivity scores, and (f) individual differences in impulsive reactivity to injected alcohol strongly predicted magnitude of voluntary alcohol intake. The findings are discussed in terms of evidence for a dysfunctional alcohol-induced positive feedback loop ("loss-of-control drinking"), alcohol disinhibition, and the relationship between impulse control and the regulation of alcohol consumption.

Behavioral Effects and Pharmacokinetics of Low-Dose Intravenous Alcohol in Humans

Alcohol has physiological effects on the human central nervous system at blood alcohol concentrations (BACs) as low as 9 mg/dl. It is unknown, however, if humans can perceive the effects of such low doses of alcohol. Furthermore, low BACs can be difficult to measure. The purpose of this experiment was to: (1) assess the ability of humans to perceive subjective effects of low BACs; (2) measure behavioral effects of low BACs on a psychomotor performance task; and (3) test the sensitivity and accuracy of the transdermal alcohol sensor (TAS) for measuring low BACs from skin. Five men and seven women were administered single-blind intravenous infusions of ethyl alcohol in 5% dextrose/water to achieve peak BACs of 0,10,20, and 40 mg/dl. Subjective intoxication scales and a computer administered continuous performance task (CPT) were used to assess alcohol effects. BACs were estimated from skin, blood, and breath. The only alcohol-induced sensation significantly increased during the alcohol infusions was anesthesia measured by the Alcohol Sensation Scale on the descending limb of the BAC curve. The subjective positive-reinforcing stimulant and mood effects of alcohol were not reported until subjects were administered the 40 mg/dl alcohol infusion. Other measures of subjective intoxication and sedation, and the CPT were unaffected by the alcohol infusions. The TAS provided a noninvasive method for estimating BACs that was comparable with estimates obtained from blood and breath, although delayed in time.