The incidence of morbid obesity has tripled over the last three decades in the developed world. In the United States alone, 65% of the population is overweight or obese. The pathophysiologic and anthropometric changes associated with obesity alter the pharmacokinetics (PK) and pharmacodynamics (PD) of numerous drugs, including IV anesthetic agents and opioids. Obese subjects have deranged cardiovascular and respiratory physiology, altering the pharmacodynamics (PD) of these drugs, and placing obese subjects at increased risk for respiratory distress and respiratory failure following administration of these agents. Recently, it has been proposed that the presence or absence of insulin resistance in obese subjects accounts for a significant amount of the heterogeneity in the obese phenotype. Together with obesity, insulin resistance increases the risk of atherosclerosis, coronary artery disease, and mortality, and accounts for changes in regional blood flow, adipose tissue distribution, and cardiac function. Adipose tissue is a highly metabolically active tissue and is responsible for the secretion of adiponectin, an adipokine with anti-inflammatory and insulin sensitizing properties. Hypoadiponectinemia is associated with diastolic dysfunction, changes in regional blood flow, and systemic hypertension, all of which may alter drug distribution. Furthermore, reductions in circulating adiponectin may serve as a marker for the insulin resistance in obese subjects. Variations in the adiponectin gene may alter quantitative adiponectin expression, and specific gene polymorphisms may serve as markers for the insulin resistant phenotype in obese subjects. The primary objective of this study is to examine the effect of insulin resistance on the PK/PD of highly lipophillic drugs (using propofol and fentanyl as models) in the obese population. We will examine the effect of quantitative adiponectin protein expression, and single nucleotide variants in the adiponectin gene on the various PK and PD phenotypes. We hypothesize that quantitative adiponectin protein expression and variants in the adiponectin gene can predict both the insulin resistant phenotype and drug response in obese subjects. This career development award will allow the candidate to gain an expertise in pharmacogenomic and translational research. The candidate has completed a research fellowship in anesthetic pharmacology, PK, and PD, and has obtained a Master of Science degree in epidemiology. A team of expert mentors has been compiled to ensure the candidate has ample support during this career development award period to meet the aims of this project and become an expert in pharmacogenomics. PUBLIC HEALTH RELEVANCE: Obese subjects are at an increased risk for adverse anesthetic drug reactions. Insulin resistance may further alter anesthetic drug dose requirements in the obese population. This project will use genetic markers to differentiate insulin resistant from insulin sensitive obese subjects, and will identify relationships between these genetic markers to anesthetic drug distribution, metabolism, and dose requirement.