A major focus of Dr. Lee’s research program involves the implementation and evaluation of CYP2C19 genotype-guided selection of antiplatelet therapy in coronary artery disease patients. An algorithm that uses clinical factors and CYP2C19 genotype to improve precision of antiplatelet therapy selection in high-risk patients undergoing percutaneous coronary intervention was implemented at our institution in 2012. Dr. George A. Stouffer (UNC Chief of Cardiology; clinical implementation of the algorithm) and Dr. Lee (data collection and analysis) have collaborated to lead this ongoing effort. Data collection and analysis is focused on evaluating the impact of genotype and clinical factors on antiplatelet drug selection, and evaluating the impact of this strategy on clinical outcomes and cost. This ongoing project includes the Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) registry, which is funded by the NIH/NHLBI in collaboration with the University of Florida.

In collaboration with the UNC Program for Precision Medicine in Healthcare, the Lee lab is also actively engaged in ongoing efforts to implement pharmacogenomics testing into clinical practice at our institution. Dr. Lee’s lab seeks to accomplish this in a manner that is evidence-based, feasible, sustainable, and amenable to the collection and analysis of data that enables continuous quality improvement, dissemination of best practices, and evaluation of impact on outcomes and cost.

Most drugs prescribed in pregnancy lack dosing information specific to this population. Dosing information is lacking, in part, because the key mechanistic factors that alter drug disposition (metabolism and transport) in pregnant people are poorly understood. This results in off-label prescribing and drug dosing, increased maternal and fetal toxicity, and reduced efficacy. Hepatic drug-metabolizing enzymes and drug transporters are integral to drug disposition. Consequently, key factors that influence hepatic drug metabolism and transport in pregnancy require systematic investigation.

Using a translational approach, ongoing projects in the Lee laboratory funded by the NIH/NICHD seek to elucidate how and to what extent pregnancy-related hormones alter hepatic metabolism and hepatobiliary disposition of clinically relevant drugs used in pregnancy that exhibit distinct clearance mechanisms in the liver. Their long-term goal is to predict pregnancy-evoked changes in hepatic drug disposition in vivo, define underlying mechanisms, and optimize drug selection and dosing in pregnant patients. A major area of the lab’s focus is on medications used to treat hypertensive disorders of pregnancy.

In parallel to the well-described cyclooxygenase and lipoxygenase pathways, cytochrome P450 (CYP) enzymes also synthesize biologically active eicosanoids in the cardiovascular system and constitute the “3rd pathway” of arachidonic acid metabolism. CYP-derived EETs and 20-HETE regulate numerous biological processes integral to the development and progression of cardiovascular and metabolic disease, such as blood pressure, inflammation, fibrosis, ischemia/reperfusion injury, angiogenesis, myocardial/vascular remodeling, and insulin resistance. Consequently, inhibitors of soluble epoxide hydrolase (sEH) and 20-HETE biosynthesis are in development.

Using a translational approach, the Lee lab seeks to obtain a deeper mechanistic understanding of these biological effects, in both preclinical models and in humans, in order to identify clinical applications for therapeutic strategies that modulate CYP-mediated eicosanoid metabolism and subsets of the population most likely to derive benefit from these experimental therapeutics.

Projects in the lab investigate the relationship between inter-individual variation in CYP-derived eicosanoids at the genetic and metabolite level and prognosis in human patients with atherosclerotic cardiovascular disease.