SCHOOL OF MEDICINE

Department of Medicine

Indiana Institute for Personalized Medicine

HIV

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. Although potential causes for variable drug effects are multiple, pharmacokinetics changes and unpredictable drug interactions that ensue are frequent and major causes of unpredictable drug effects. The majority of currently marketed drugs are eliminated primarily by metabolism. Therefore, the main research focus of Dr. Desta's laboratory is the identification of genetic and non-genetic mechanisms of interindividual variability in drug disposition, drug-drug interaction and response.

Special emphasis is given to the cytochrome P450 (CYP) superfamily, which catalyzes the monooxygenation of a large number of clinically important drugs, environmental chemicals of toxicological significance (e.g., chemical carcinogens and pesticides) and endogenous substances (e.g. steroids, leukotrienes, eicosanoids and fatty acids) that play an important role in physiological processes. The human CYP superfamily contains 57 functional genes, but members from three families of CYPs, CYP1, CYP2 and CYP3 are the main contributors to the oxidative metabolism of clinical used drugs and thus are the focus of our studies. Therefore, our goal is the improved understanding of the mechanisms of interindividual variability of these enzymes will contribute to better manage drug therapy for the individual patient.

The laboratory is currently investigating role of pharmacogenetics of drug metabolism in response to endocrine therapy of breast cancer (tamoxifen and aromatase inhibitors) and antiretroviral drugs (e.g. nonnucleoside reverse transcriptase inhibitors). The lab is particularly interested in the interplay between genetic variations in drug metabolism and drug interactions. We have also been developing phenotyping tools to study the function of CYPs in vitro and in vivo. So far we have discovered the following probes: efavirenz and letrozole as probes for CYP2B6 and CYP2A6 respectively, thioTEPA and voriconazole as inhibitors of CYP2B6, letrozole as selective inhibitor of CYP2A6, and the [13C]-pantoprazole breath test as noninvasive test for CYP2C19 activity in vivo.