Speaker: Kenneth Brouwer
Dr. Brouwer has over 25 years’ experience in preclinical drug development and is a co-founder of Qualyst, a provider of hepatic drug transporter products and research services. Prior to founding Qualyst, Dr. Brouwer served as Executive Director, Drug Metabolism and Pharmacokinetics at PPD Discovery, where he directed research in metabolism, pharmacokinetics, toxicology, and absorption technologies.
Previously he served as Director, Preclinical Development, Drug Metabolism and Pharmacokinetics at GlaxoSmithKline and was responsible for the drug metabolism and pharmacokinetics strategy leading to candidate selection, review of candidate project plans prior to candidate selection, and developing and implementing process to ensure a smooth transition from candidate selection to full development.
Dr. Brouwer has over 25 publications in peer reviewed journals, holds two patents, serves on the Editorial Advisory Board for the Journal of Pharmaceutical Sciences, and is an adjunct faculty member in the Division of Drug Delivery and Disposition at the School of Pharmacy, University of North Carolina.
In this webinar, Kenneth Brouwer talks about the evaluation of BSEP inhibition and how to identify drug candidates that could induce cholestatic liver toxicity. There are multiple examples of potent BSEP inhibitors (based on vesicle data) that do not result in cholestatic liver injury. Utilizing Transporter Certified™ human hepatocytes under conditions that allow for repolarization of the hepatocytes (sandwich culture) we are able to correctly identify compounds with the potential to cause cholestatic hepatotoxicity. In addition to the inhibition of BSEP, interference with the adaptive response through antagonism of FXR or inhibition of basolateral efflux may be needed to cause an increase in the intracellular concentration of bile acids which leads to cholestatic hepatotoxicity. Integration of a compound’s effect on the adaptive response greatly increases the predictive potential for cholestatic hepatotoxicity. This presentation will review the conditions necessary for a predictive assay, and present results from an initial screening data set.View on demand
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