Specific Aims: A study of the interaction of overnutrition (obesity) and psychotropic drug disposition on selected model drugs (antipyrine, acetaminophen, lidocaine), minor tranquilizers (benzodiazepines), and tricyclic antidepressants is proposed. Model drugs represent oxidative (antipyrine), conjugative (acetaminophen), and restrictive (hepatic blood flow limited) (lidociane) drug metabolism. Psychotropic drugs are commonly used in this population and are highly fat soluble, metabolized by both oxidative and conjugative pathways, and the tricyclic antidepressants have high first-pass metabolism, implying some dependence on hepatic blood flow for clearance. Methjodology: (1) Obese and control subjects will undergo single-dose pharmacokinetic studies of drugs listed above. Using iterative non-linear least-squares methods, kinetic parameters between matched cohort populations will be compared by parametric methods such as Student's t-test. (2) Obese patients receiving benzodiazepines and tricyclic antidepressants will have steady-state drug levels determined and entered into multiple regression analysis with patient weight, height, age, concurrent drug usage, drug dose and biochemical data to identify sources of variability in the drug dose-plasma level relationship. (3) In vitro physichemical parameters (octanol:aqueous buffer partition; liquid chromatographic retention index) will be determined for psychotropic drugs as measures of their lipid solubility. These parameters will be evaluated for relations between in vivo drug distribution and biotransformation. Long-term Objectives: A relation between drug lipid solubility and extent of distribution in overnutrition may exist, and clearance of conjugatively metabolized drugs may be increased as well. The interaction of obesity andpsychotropic drug distribution and clearance will be correlated with in vitro determinants of drug physicochemical properties. This may provide a means of predicting pharmacokinetic parameters in the overnourished. This ay provide a means of predicitng pharmacokinetic parameters in the overnourished. Thus dose regimens for these psychotropic drugs when patient nutritional status and the mode of metabolism of an individual drug is know will permit more effective psychotropic drug therapy in this large patient population.