The goal of effective and safe therapy of many drugs is made difficult by large interindividual variability in response to these drugs and is of major concern for patients, and their caretakers and significantly adversely influences the cost of health care. Our ultimate goals are comprehensive understanding of mechanisms controlling interindividual variability in drug response and then apply this knowledgebase to maximize beneficial and minimize adverse effects of medications for the individual patient. Although potential causes for variable drug effects are multiple, interpatient differences in drug disposition and unpredictable drug-drug interactions (DDIs) are frequent and major determinants of beneficial and adverse drug effects. Thus, our research focuses on identifying factors that contribute to variable drug disposition. Completed and ongoing bench and clinical studies in our laboratory address the impact of altered drug metabolizing enzymes and drug transporters due to genetic polymorphisms and nongenetic factors (e.g., DDIs) on exposure of drugs and (active) metabolites. Our research activities include: developing new analytical tools to measure drugs and their metabolites; profiling of drug metabolites; identification of rate limiting metabolic pathways and the specific enzymes involved; developing and validating novel molecular and clinical tools to study drug disposition and DDIs; assessing the impact of genetic variants and DDIs as well as interplay of them on drug exposure and effect; and developing mathematical models (e.g. static models, PBPK and popPK) to allow mechanistic understanding and quantitative prediction of clinical drug exposure and DDIs from in vitro data. Basic discoveries are made using in vitro model systems. Then, complementary clinical studies are designed in healthy volunteers at the Indiana Clinical Research Center or in patients to verify clinical significance. Dr. Desta has >20 years of experience and extensive publication record (> 130 peer-reviewed) in this area of this research. Our laboratory has made seminal discoveries including new active metabolites (e.g., endoxifen), multiple in vitro and in vivo biochemical, clinical and genetic approaches to study CYPs, and clinical studies that lead to changes in FDA drug labelling (e.g., tamoxifen, pimozide, and efavirenz). We have continuously competed and received funding from the NIH as a PI or Co-I to pursue collaborative research.