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 subject?s 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. ? ? The overall goals of this research are: (1) evaluate the genetic and environmental determinants of variability in the metabolism and pharmacokinetics of alcohol in humans, using the IV alcohol clamp and advanced pharmacokinetic modeling methods, and (2) utilize behavioral, neuroendocrine, electrophysiological and functional imaging measures of the CNS pharmacodynamics of alcohol in humans, to examine genetic and environmental risk factors and neuroadaptive processes related to the development of alcoholism.? ? An ongoing study aims to evaluate the influence of sex and age on the metabolism and acute response to alcohol, using the alcohol clamp method in social drinkers. 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 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.
