Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy Volunteers
ABSTRACT Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject.
This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual's physiology. The peak BrACs (C(max)), times of peak BrAC (T(max)), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol.
The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean C(max), T(max), and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in C(max) and AUC were both 11%, while the mean %difference for T(max) was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%].
Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response.
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ABSTRACT: Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5' and 3' functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs / ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage.Pharmacology Biochemistry and Behavior 11/2013; 123. DOI:10.1016/j.pbb.2013.11.001 · 2.82 Impact Factor
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ABSTRACT: Background This study is a review of alcohol dispersion into and elimination from the fetal compartment. Methods PubMed searches were conducted for all years and all languages for relevant papers. We also hand searched the reference list of papers and text books for additional references. ResultsAlcohol concentration is determined by body water (49% for women), grams of ethanol consumed, and duration of drinking. The fetus has very limited metabolic capacity and transfer from the fetal compartment to maternal circulation is the major pathway to reduce fetal exposure. Vasoconstriction of the placenta-umbilical unit from alcohol and smoking decreases rates of alcohol elimination from the fetal compartment. By 20 weeks of gestation, keratinization of fetal skin reduces the permeability of fetal skin to very low levels, increasing the duration of fetal exposure and complicating alcohol elimination from the fetal compartment. Two reabsorption pathways, the intramembranous pathway and fetal swallowing, create a recycling system where much of the ethanol the fetus excretes will be reabsorbed back into its circulatory system. Fetal re-excretion of ethanol into the amniotic fluid occurs by means of fetal urine, breathing movements, and nasal excretions. Amniotic fluid then functions as a reservoir for ethanol, prolonging fetal exposure. Conclusion While the fetus has the ability to metabolize some ethanol, removal from the fetal–maternal unit relies primarily on maternal metabolic capacity. The alcohol elimination rate from the fetal compartment is approximately 3% to 4% of the maternal rate. We conclude with examples of the clinical relevance of information from this review. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.Birth Defects Research Part A Clinical and Molecular Teratology 04/2014; 100(4). DOI:10.1002/bdra.23232 · 2.21 Impact Factor
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ABSTRACT: Human laboratory and animal models implicate variation in the μ-opioid receptor gene (OPRM1) as relevant for alcohol-related reward. OPRM1 is associated with alcohol self-administration in non-human primate studies, but the relevance of this finding to human models is unclear. This study used computer-assisted self-infusion of ethanol (CASE) to examine associations among OPRM1 A118G genotype, subjective responses to alcohol and intravenous alcohol self-administration in young heavy drinkers (n = 40, mean age = 19.95 years, SD = 0.82). Participants completed a 2-hour CASE session comprising a priming phase followed by ad libitum self-administration in a free-access paradigm. Participants achieved a mean peak breath alcohol concentration (BrAC) of 81.18 mg% (SD = 24.96). Those with the OPRM1 118G variant (GA or GG genotypes) achieved significantly higher peak BrAC (M = 94.90 mg%, SD = 16.56) than those with the AA genotype (M = 74.46 mg%, SD = 25.36), reflecting a significantly greater number of alcohol requests among GA/GG participants. Eighty percent of GA/GG participants surpassed a threshold defining a laboratory analog of heavy alcohol exposure (80 mg%) compared with 46 percent of AA participants. Results indicated significant associations between subjective measures of alcohol sensitivity and CASE outcomes, although the pattern of findings differed across self-report measures. Subjective responses did not differ by OPRM1 status. These results offer further support for the feasibility of the CASE paradigm and provide initial evidence for an association of OPRM1 with alcohol self-administration in a human laboratory context.Addiction Biology 08/2014; DOI:10.1111/adb.12165 · 5.93 Impact Factor