Pharmacokinetics and Responses to Alcohol After Bariatric Surgery

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ABSTRACT More than two million Americans have undergone bariatric surgery over the last decade; given the obesity epidemic, this number will continue to rise. Since 2018 of the ~ 250,000 yearly bariatric procedures performed in the United States, 72% are sleeve gastrectomy (SG) and 21% Roux-en-Y gastric bypass (RYGB). Although these surgeries provide the most successful long-term treatment for obesity, they double the risk of developing alcohol use disorders (AUD). The precise mechanism(s) underlying an increase AUD risk is uncertain, but in our previous NIH-funded research in women who underwent these surgeries (AA024103), we demonstrated that both SG and RYGB cause profound changes in alcohol pharmacokinetics (PK) and sensitivity to the subjective effects of alcohol; both of which can increase AUD risk. RYGB and SG doubled peak blood alcohol concentrations when consuming the same dose as before surgery. By studying PK after SG, we also help clarify that most alcohol first-pass metabolism (FPM) occurs in the stomach, not the liver (at least in women), providing a plausible mechanism for increased alcohol-related liver disease and AUD after surgeries that reduce the stomach. In people who did not undergo SG/RYGB, drinking alcohol with a meal increases FPM and the alcohol elimination rate (AER), thus reducing alcohol bioavailability and intoxication. However, the effects of food on alcohol PK after SG are unknown. SG alters nutrient absorption leading to earlier and higher glycemic peaks concomitant with exaggerated postprandial insulin rises that can trigger postprandial hypoglycemia. Because alcohol inhibits gluconeogenesis, we posit that drinking alcohol with food will increase the risk for hypoglycemia after SG. In addition, there are remarkable sex-related differences in alcohol PK, but previous bariatric studies included only women or very few men to determine sex differences. Therefore, the primary goal of the proposed study is to determine sex-related differences in the impact of SG on the PK (Aim 1), subjective effects (Aim 2), and glycemic effects (Aim 3) in the fasted versus prandial state when alcohol is ingested or given intravenously clamped (the gold standard to measure AER and acute alcohol tolerance). We will use a cross-sectional study to compare participants who underwent SG surgery 1-5 years ago with matched non-operated controls (both sexes). Our main hypotheses are that compared to controls, in the SG group, food will 1) increase less FPM (particularly in men) and decrease less the sedative effects of ingested alcohol, 2) amplify alcohol-hypoglycemia and acute tolerance to the sedative effects when alcohol is given IV (in the clamp). This project will answer the questions of whether there are sex-related differences in the impact of SG on alcohol’s PK and pharmacologic effects, whether drinking alcohol with a meal is effective or counterproductive post-SG (considering risk for hypoglycemia) and clarify the site of FPM in men. Findings from this study will contribute to evidence-based recommendations on the impact of SG on alcohol-related toxic effects and could help expand the knowledge base of sex-related differences in human alcohol PK.