The pharmacokinetics of alcohol have been the evaluated extensively in humans. Studies have emphasized the high (2-3 fold) inter-individual and intra-individual variation in the pharmacokinetics of alcohol, including alcohol absorption and metabolic rates. Most of this variation can be attributed to factors that include, but are not limited to, alcohol intake, food consumption and composition, use of other drugs, sex, age, body weight, body composition, as well as genetic polymorphisms of the alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ? ? The pharmacodynamic effects of alcohol, particularly the CNS effects, have also been studied extensively, both following acute as well as chronic alcohol use. A variety of behavioral, endocrine and physiological measures have been used to examine the variability in alcohol responses, and to examine the genetic and environmental determinants of the effects of alcohol. In order to characterize the response to alcohol, it is important to control the variability in the absorption and metabolism of alcohol and the resulting blood (and therefore brain) alcohol exposure that drives the pharmacological effects of alcohol.? ? The alcohol clamp is a method that uses an intravenous infusion of alcohol to achieve and maintain a pre-determined target breath alcohol concentration for a prescribed duration of time. The alcohol infusion rate is based on a physiologically-based pharmacokinetic model for alcohol and is computed using individualized estimates of the model parameters, which are based on the subjects height, weight, age and gender. Serial breathalyzer measurements ensure that the BrACs are within 5% of the target, and to enable minor adjustments to the infusion rates to overcome errors in parameter estimation and experimental variability. During the alcohol clamp, the steady-state alcohol infusion rate that results in a constant BrAC exposure is a measure of the alcohol elimination rate. Thus the alcohol clamp provides a unique platform for evaluating the genetic and environmental determinants of the pharmacokinetics and pharmacological effects of alcohol in humans. ? ? Ongoing Studies: Influence of sex and age on alcohol metabolism and responses? ? Previous research indicates that alcohol metabolism differs between men and women, and may be influenced by age as well. There appears to be a complex interaction between sex, age and alcohol metabolism, and differences in sex steroidal hormones, estrogen and testosterone, may underlie this interaction. Studies have also shown sex- and age-related differences in the response to alcohol, although the underlying determinants of these differences are unclear. The elderly are thought to be more sensitive to alcohol and show greater impairment than younger groups. However, it is not clear if these changes are due to pharmacokinetic or pharmacodynamic factors. ? ? The objective of this study is to evaluate the influence of sex and age on the metabolism and acute response to alcohol, using the alcohol clamp method in social drinkers. The study is a randomized, two-session crossover study in 48 participants: twenty-four young, 21-25 year-old social drinkers (12 male and 12 female) and 24 older, 55-65 year-old social drinkers (12 male and 12 female). In one session, participants will receive an IV infusion of ethanol, individualized to achieve and maintain a steady-state breath alcohol concentration (BrAC) of 50 mg% for 3 hrs. In the other session participants will receive saline. The alcohol elimination rate and response to alcohol on behavioral and physiological measures will be evaluated. The ongoing study will provide valuable information about the effects of age and sex on alcohol metabolism and response. Findings from these studies will provide a better understanding of age- and sex-related differences in metabolic processes, which may underlie medically important differences in the responses of individuals to alcohol. ? ? Preliminary analyses have been conducted to evaluate sex differences in AER in the 21-25 year-old group and to evaluate age-related differences in AER in males (only 5 of 12 females in the 55-65 year-old age group have completed the study thus far). Results of these analyses indicate that alcohol elimination rates were significantly higher in males than in females in the younger age group, as expected. AER normalized for lean body mass was similar between males and females, indicating that sex differences in AER may be accounted for, in part, by sex differences in lean body mass. Age does not appear to influence AER in males. Lean body mass explained approximately 53% of the variance in AER across females and young and older males.? ? Future plans for this study include completion of subject enrollment and data collection, and analyses to examine age effects in female social drinkers as well as sex effects in older male and female social drinkers. Additional analysis will evaluate the role of liver volume and sex steroid levels on alcohol elimination rates in males and females. Finally, analysis, including pharmacokinetic-pharmacodynamic modeling, will be conducted to evaluate the influence of age and sex on subjective perception and heart rate changes during the alcohol clamp.? ? This study will provide valuable information about the effects of age and sex on alcohol metabolism and response. Findings from these studies will provide a better understanding of age- and sex-related differences in metabolic processes, which may underlie medically important differences in the responses of individuals to alcohol. ? ? Additional Studies:? ? Two additional studies, employing the alcohol clamp method, aimed at evaluating the pharmacological effects of alcohol on imaging measures are underway. The first is a study evaluating the effect of alcohol on cerebral blood flow using functional magnetic resonance imaging (fMRI), in healthy social drinkers (Daniel Hommer, PI). This project aims to evaluate the BOLD response during an alcohol clamp, under basal conditions and during a task designed to elicit positive and negative emotions. The other study is aimed at evaluating the dopamine release, using 11C-raclopride displacement and positron emission tomography (PET) during an alcohol clamp, and the effect of genetic polymorphism of the mu-opioid receptor gene (A118G) on the response to alcohol in healthy social drinkers (Markus Heilig, PI).? ? ? Future Directions:? ? The Unit continues to support studies utilizing the alcohol clamp for evaluating the pharmacodynamics of alcohol. This includes a proposed study to evaluate the effect of treatment with opiate antagonists on brain activation in response to acute IV alcohol administration in alcohol-dependent individuals. Another study aims to examine the effect of acute alcohol exposure, using the alcohol clamp, on fMRI correlates of positive and negative emotional responses in healthy social and heavy drinkers.? ? In addition to the above, the Unit is also developing studies to evaluate a new mode of alcohol administration to assess alcohol self-administration behavior in humans.? The CASE paradigm enables the examination of self-administration behavior in humans under conditions of minimal pharmacokinetic variation, and can be a valuable tool for evaluating factors such as sex, age, family history of alcoholism, drinking history and genetic variation, that may underlie self-administration behavior in humans. The effect of pharmacological agents on the rate, magnitude and pattern of exposure to alcohol achieved in individuals under this paradigm can be evaluated as a biomarker of the clinical effectiveness of these agents in the treatment of alcohol-dependence.
