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Importance of Hepatic Transporters, Including Basolateral Efflux Proteins, in Drug Disposition: Impact of Phospholipidosis and Non-Alcoholic Steatohepatitis

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Importance of Hepatic Transporters, Including Basolateral Efflux Proteins, in Drug Disposition: Impact of Phospholipidosis and Non-Alcoholic Steatohepatitis IMPORTANCE OF HEPATIC TRANSPORTERS, INCLUDING BASOLATERAL EFFLUX PROTEINS, IN DRUG DISPOSITION: IMPACT OF PHOSPHOLIPIDOSIS AND NON-ALCOHOLIC STEATOHEPATITIS Brian C. Ferslew A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmaceutical Sciences in the UNC Eshelman School of Pharmacy Chapel Hill 2014 Approved by: Dhiren Thakker Mary F. Paine A. Sidney Barritt Kim L.R. Brouwer Jo Ellen Rodgers Wei Jia ©2014 Brian C. Ferslew ALL RIGHTS RESERVED ii ABSTRACT Brian C. Ferslew: Importance of Hepatic Transporters, Including Basolateral Efflux Proteins, in Drug Disposition: Impact of Phospholipidosis and Non-Alcoholic Steatohepatitis (Under the direction of Kim L.R. Brouwer) The objective of this dissertation project was to develop preclinical and clinical tools to assess the impact of liver pathology on transporter-mediated systemic and hepatic exposure to medications. A translational approach utilizing established pre-clinical hepatic transport systems, mathematical modeling, and a pivotal in vivo human study was employed. A novel application of rat sandwich-cultured hepatocytes (SCH) was developed to evaluate the impact of drug-induced phospholipidosis on the vectorial transport of probe substrates for hepatic basolateral and canalicular transport proteins. Results indicated that rat SCH treated with prototypical hepatic phospholipidosis inducers are a sensitive and selective model for drug-induced phospholipidosis; both organic anion transporting polypeptide-mediated uptake and bile salt export pump-mediated biliary excretion were reduced after the onset of phospholipidosis. Enalapril currently is being investigated for its anti-fibrotic effects in the treatment of patients with non-alcoholic steatohepatitis (NASH). Although the basolateral uptake transporters responsible for enalapril entry into the hepatocyte are well characterized, less is known about translocation of enalaprilat (the active metabolite) across the basolateral membrane into the systemic circulation. Studies were conducted using membrane vesicles prepared from transporter-expressing cells and a novel human SCH efflux protocol to assess the involvement of two hepatic basolateral efflux transporters known to be up-regulated in inflammatory liver disease [i.e., multidrug resistance-associated protein (MRP)3 and MRP4]; enalaprilat is transported across the basolateral membrane, in part, by MRP4. A novel clinical protocol was developed using morphine glucuronides as a probe for MRP3 function to determine the impact of altered hepatic transporter expression on drug disposition in patients iii with NASH. A physiologically-based mathematical model was constructed to inform study design. Systemic concentrations of morphine glucuronides were increased significantly in patients with NASH compared to healthy subjects, as predicted by the model. This work provides a mechanistic understanding of the impact that hepatic transporter function has on the disposition of drugs and endogenous compounds under normal conditions and in response to altered liver function due to drug- induced phospholipidosis or liver disease, specifically non-alcoholic steatohepatitis. This knowledge is fundamental to safe and efficacious dosing of medications that depend on these transporters for disposition and/or elimination. iv To my family, who enabled and provided guidance. Thank you for your unwavering support and encouragement. v ACKNOWLEDGEMENTS I want to thank Kim Brouwer for the opportunities she helped me to realize during this research project. I also want to thank my committee members for their invaluable support and contributions, both scientific and personal, during my graduate tenure: Mary Paine, my early committee chair, who was always available for scientific discussion, but also demanded quarterly updates to keep me on track scientifically and personally; Dhiren Thakker for taking over as my committee chair without hesitation and providing critical and objective advice; Jo Ellen Rodgers for always advocating for my progression through the program; Wei Jia for his ability to provide excellent scientific insight from a different perspective and outstanding collaboration; and Sid Barritt for his ability to condense complex ideas and problems down to specific actionable steps and providing clinical expertise spanning my research project. The specific and generalized contributions from this diverse committee have guided my personal and scientific growth. Thank you for everything! I would be amiss without acknowledging the help of my friends and colleagues, both past and present, who assisted in this research along the way. I want to thank Nathan Pfeifer for his friendship and support through my graduate studies. Thank you for everything you have done for me from spending countless hours at Weaver Street Market doing what people do there to being a scientific sounding board. I could not have asked for a better colleague and friend. I also want to sincerely thank Curtis Johnston. Curtis, I could not have done the work detailed herein without you. Your ability to calmly and systematically address issues is inspiring. Thank you for your unwavering and very timely help in all aspects. Many times I was struggling to keep up with you and feel this strengthened my research drastically. I hope that you were able to learn as much from me as I did from you. Additionally I would like to thank my late roommate, Ellie Exner. Your support through my tenure has been truly exceptional. vi Selflessly helping me through the most trying times experimentally, professionally and personally are far more than I could have expected. Additionally I need to acknowledge many others that have taught me a great deal: Julie Dumond, Kathleen Köck, Arlo Brown, Kathy Maboll, Danny Gonzalez, Brandon Swift, Tracy Marion, Kevin Watt, and Eleftheria Tsakalozou. Finally, I would like to thank two inanimate objects (or maybe the people/animals behind them) for their ability to provide me a place devoid of distractions to clear my mind. Garland Pobletts thank you for allowing me to use the mountain house ad libitum. Many long weekends were spent doing the things I love without interruption. And to the bunny who kept my garden interesting. Although we had many standoffs, focusing on outsmarting you, a rabbit, was humbling. I have the utmost respect and sympathy for Elmer Fudd. Lastly, I need to thank the people that helped me to get here and kept everything in perspective. Jayme Hostetter, thank you for your patience with me and listening ear throughout. You always found a way to calmly work through problems and obstacles. Long standing friends who have never judged or asked me to explain, but instead offered their support time and time again: David McGowan from 3rd grade, I have relied on you to remind me to have fun; George Francisco for being the impetus for getting myself into this mess, but also for being a solid sounding board; and Matt Felbringer for never a dull moment. Finally, to my family; the people that got me here and through, through my best and worst. The family you have built has enabled us so much! I cannot say thank you enough. Matthew, thank you for all the advice and help, whether you knew it or not. From not getting scolded for coming home late (yes, you bore the brunt of that) to how to handle tough situations to when best to wax my new car, learning from your lead has kept me on a relatively straight path. Just please don’t swing the bat again when I’m walking by. Dad, thank you for your support. Thank you for listening and guiding, but allowing me to forge my own path. Grandpa seems to have influenced many generations with his saying, “What do you think?”. Mom, I don’t need to expand on you; I could not have finished this without you. vii TABLE OF CONTENTS LIST OF TABLES ........................................................................................................................................ x LIST OF FIGURES ..................................................................................................................................... xi LIST OF ABBREVIATIONS ..................................................................................................................... xii CHAPTER 1. Introduction: Drug Transport in the Liver ............................................................................ 1 Hepatic Physiology: Liver Structure and Function ................................................................................ 1 Hepatic Uptake Transport Proteins ........................................................................................................ 2 Hepatic Efflux Transport Proteins .......................................................................................................... 4 Regulation of Hepatic Drug Transport Proteins ..................................................................................... 8 Disease State Alterations in Hepatic Transport Proteins ...................................................................... 12 Model Systems for Studying Hepatobiliary Drug Transport ................................................................ 18 Drug Interactions in Hepatobiliary Transport ...................................................................................... 25 Interplay Between Drug Metabolism and Transport ...........................................................................
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