November 8, 2017
Kim L.R. Brouwer, Pharm.D., Ph.D., has received an Outstanding Investigator Research Award from the National Institute of General Medical Sciences. The award is a National Institutes of Health R35 Senior Investigator Award worth $2.6 million over five years.
Brouwer is the W.R. Kenan Jr. Distinguished Professor in the Division of Pharmacotherapy and Experimental Therapeutics and the School’s associate dean for research and graduate education. The project is titled “Mechanisms of altered hepatic transport: Impact on drug therapy” and will run through the end of March 2022.
The study will answer key questions related to the hepatic transport of bile acids and medications, provide new mechanistic information and develop novel predictive tools, Brouwer said.
“Hepatic transport proteins are critical determinants of drug exposure, efficacy and harmful side effects, such as liver toxicity,” Brouwer said. “The influence of medications, genetic variation and disease on the function of these proteins is poorly understood. This research will contribute to more efficient development of safer and more effective medications.”
The importance of hepatobiliary transport proteins in medication disposition, safety and efficacy is well recognized, Brouwer said, and identifying key hepatic transporters involved in these processes and understanding the factors that affect their function is critical to successful drug development and optimal pharmacotherapy.
The overall goal of the research program funded by this NIGMS grant is to address major knowledge gaps in hepatobiliary drug transport and develop novel strategies to assess and predict the impact of transporter function altered by drug interactions, genetic variation and disease, Brouwer said. This information is fundamental to the science of precision medicine and will aid in preventing drug interactions and drug-induced liver injury.
“My laboratory pioneered the use of sandwich-cultured hepatocytes, a powerful in vitro tool now widely used to study hepatobiliary drug transport and hepatic transporter-mediated drug interactions,” she said. “We were the first to assess the functional impact of nonalcoholic steatohepatitis-associated increases in hepatic basolateral efflux transporter expression on drug/metabolite disposition in humans and to utilize human liver scintigraphy data to evaluate hepatic drug interactions.”
Brouwer’s team is developing computational tools that can be used in early drug development to identify compounds with drug-induced liver injury liability. They have formulated a strategy integrating physiological parameters and experimental data with a quantitative systems pharmacology model to evaluate the mechanisms of drug-induced liver injury. These highly innovative approaches can improve predictions of hepatic transporter-mediated drug interactions and drug-induced liver injury liability, leading to safer medications.