Dr. Kim’s research is focused on understanding the molecular determinants of interindividual variation in drug response. Using a pharmacogenomics approach, this lab combines research on drug metabolism and transport with research on the influence of genetic variation on drug response to develop personalized drug therapies for cancer, vascular disease, and adverse drug reaction prevention.
Current projects include: Researching the pharmacogenetic and pharmacokinetic variability of aromatase inhibitors in patients with breast cancer
: While these drugs are effective for treating breast cancer, they can cause adverse drug reactions in some patients, including musculoskeletal problems such as myalgia and arthralgia. Understanding the pharmacogenetic and pharmacokinetic variability of aromatase inhibitors in patients has the potential to better predict those at risk for adverse drug reactions. Investigating the safety and efficacy of a new and increasingly prescribed generation of oral anticoagulants used for stroke prevention
: Our research goals are to measure drug levels of direct oral anticoagulants (apixaban, rivaroxaban and dabigatran) in patients to determine the pharmacokinetic variation in a real-world clinical setting, as well as identify the clinical and/or genetic factors that are predictive of excessive or sub-therapeutic drug exposure. This information will be used to develop a predictive algorithm for optimal dose selection of these medications. Examining genetic predictors of risk for cisplatin-induced ototoxicity in head and neck cancer
: Cisplatin-based chemoradiotherapy remains a standard treatment for head and neck cancers. However, use of cisplatin is complicated by serious side effects, including nephrotoxicity and ototoxicity, resulting in dose delay, reduction and premature discontinuation. Ototoxicity is currently not predictable and may cause permanent hearing loss. Some patients experience severe hearing loss after their first dose of cisplatin while others have a delayed toxicity onset or none at all. We are interested in using sequencing technologies, including Next-generation sequencing (NGS), to identify genetic predictors of ototoxicity. Determining the effect of concomitant food administration, and the type of food administered, on the blood exposure of rosuvastatin
: Clinical use of statin medications surpasses any other drug class in North America for the treatment of high cholesterol. Patients receiving statins may experience muscle pain or even muscle breakdown causing discomfort and limiting compliance to the medication. This study will determine the effect of food on rosuvastatin exposure. We predict that taking rosuvastatin with food will increase its uptake into the liver (its site of action), thereby reducing the amount of drug available to reach skeletal muscle. This may reduce muscle related side effects commonly associated with rosuvastatin use. Additionally, this study will explore a possible bile acid related mechanism for this food effect from which subsequent studies may develop food-independent therapies for enhanced liver uptake of rosuvastatin.Dr. Richard Kim: Biography
The Tirona lab has two main research focuses: Drug disposition in non-alcoholic fatty liver disease (NAFLD)
. NAFLD is the most common liver disease in the developed world, affecting 30% of the Canadian population. Given the close association with metabolic syndrome and increased risk of cardiovascular disease, many NAFLD patients are prescribed a variety of medications to manage these comorbidities. The liver is the primary site of drug metabolism and yet, surprisingly, we know little about how NAFLD affects drug response. In collaboration with Dr. Melanie Beaton in the Division of Gastroenterology, we are studying the pharmacokinetics of drugs in patients with NAFLD. Furthermore, we perform studies in animal models and cellular systems to understand the molecular mechanisms involved in altered drug disposition in NAFLD. Role of Organic Anion Transporting Polypeptide 2B1 (OATP2B1) in drug disposition
. OATP2B1 is a widely expressed drug transporter that facilitates the uptake of solutes into cells. In the intestine and liver, OATP2B1 is considered to play a role in promoting oral drug absorption and hepatic elimination, respectively. We have developed a mouse model whereby the gene encoding oatp2b1 (slco2b1) is disrupted, in order to understand the in vivo relevance of this transporter in the pharmacokinetics of drugs. We are also studying how the expression of the SLCO2B1 gene is regulated at the molecular level.
Dr. Tirona Rommel: Biography
Dr. Schwarz’s research is focused on understanding the role of organic anion-transporting polypeptide (OATP) uptake transporters in insulin secretion and pancreatic islet cell function.
The Schwarz lab is currently working on the characterization of transporter expression in the human pancreatic islet as well as their role in statin-induced impairment of beta cell function. Statins are commonly prescribed to lower cholesterol through 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibition. Though effective and safe for most, recent evidence suggests an increased risk of new-onset diabetes in patients on statin therapy. While the exact molecular mechanisms have not been elucidated, the role of coenzyme Q10 (CoQ10) in modulating islet beta cell function offers an intriguing link. Statin-induced, beta cell depletion of CoQ10 is thought to diminish adenosine triphosphate (ATP), leading to decreased ATP-dependent potassium channel function, membrane depolarization and calcium influx resulting in reduced insulin secretion.
Organic anion-transporting polypeptides (human OATPs, rodent Oatps) mediate cellular uptake of statins, and some isoforms (OATP1B3, OATP2B1, Oatp1a1, Oatp1a4, Oatp1a5) were recently reported in human and murine pancreatic islets. This research utilizes different cell-based and transgenic mouse models employing both knock out and knock in strategies. Furthermore, Dr. Schwarz studies the role of these uptake transporters in the progression and chemosensitivity of pancreatic cancer, and their potential as a diagnostic marker and therapeutic target.Dr. Ute Schwarz: Biography