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Mechanisms of Drug-Induced Liver Injury: the Role of Hepatic Transport Proteins

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Mechanisms of Drug-Induced Liver Injury: the Role of Hepatic Transport Proteins MECHANISMS OF DRUG-INDUCED LIVER INJURY: THE ROLE OF HEPATIC TRANSPORT PROTEINS Kyunghee Yang 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 Eshelman School of Pharmacy Chapel Hill 2014 Approved by: Kim L.R. Brouwer Paul B. Watkins Dhiren Thakker Harvey J. Clewell III Brett A. Howell ©2014 Kyunghee Yang ALL RIGHTS RESERVED ii ABSTRACT Kyunghee Yang: Mechanisms of Drug-Induced Liver Injury: The Role of Hepatic Transport Proteins (Under the direction of Kim L.R. Brouwer) The objectives of this research were to investigate mechanisms of drug-induced liver injury (DILI) that involve drug-bile acid (BA) interactions at hepatic transporters, and develop a novel strategy to reliably predict human DILI. Troglitazone (TGZ), an antidiabetic withdrawn from the market due to severe DILI, was employed as a model hepatotoxic drug. Pharmacokinetic modeling of taurocholic acid (TCA, a model BA) disposition data from human and rat sandwich-cultured hepatocytes (SCH) revealed that species differences exist in TCA hepatocellular efflux pathways; in human SCH, TCA biliary excretion predominated, whereas biliary and basolateral excretion contributed equally to TCA efflux in rat SCH. This finding explains, in part, why rats are less susceptible to DILI compared to humans after administration of drugs that inhibit BA biliary excretion. The present study also revealed for the first time that TGZ sulfate (TS), a major TGZ metabolite, inhibits BA basolateral efflux in addition to biliary excretion. These findings support the hypothesis that TS is an important mediator of altered hepatic BA disposition; increased hepatic TS exposure due to impaired canalicular transport function might predispose a subset of patients to hepatotoxicity. A novel in vitro model system, rat SCH lacking selected canalicular transporters [breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2)] was established to test this hypothesis; biliary excretion of hepatically-generated TS was not significantly altered, suggesting that alternate transporters can excrete TS into bile, and loss of Bcrp and/or Mrp2 function would not necessarily be risk factors for increased hepatocellular TS accumulation in rats. To translate experimental data to in vivo humans, a mechanistic model that incorporated TGZ/TS disposition, BA physiology/pathophysiology, hepatocyte life cycle, and liver injury iii biomarkers was developed; intracellular BA concentrations and toxicity measured in SCH were used to link BA homeostasis and hepatotoxicity. This mechanistic model adequately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity. This dissertation research revealed a number of important and novel findings that improve our understanding about mechanisms underlying BA-mediated DILI, and establish a framework to integrate biological information and experimental data to evaluate DILI mechanisms and predict hepatotoxic potential of chemical entities. iv ACKNOWLEDGEMENTS First of all, I want to thank Dr. Kim Brouwer for her constant support, guidance, and encouragement, and for having been there as a great mentor at every stage of my growth over the last four years. I also want to thank all the members of my dissertation committee who have been influential on my scientific and personal development: Dr. Watkins for serving as my chair and all of the guidance, advice, and opportunities he has provided during my dissertation research and also for future career; Dr. Thakker for insights on drug metabolism and transport, and exciting scientific discussions; Dr. Howell for all of the modeling advice and expertise which have enabled me to carry out the mechanistic modeling project; Dr. Clewell for all of the helpful comments and insights on pharmacokinetic modeling; Dr. Paine for serving as my early committee and continuing support. This dissertation would not have been possible without the help of so many people in so many ways. I would like to thank the past and present Brouwer lab members, for intellectual interactions as well as being such great lab mates: Grace Yan, Tracy Marion, LaToya Griffin, Wei Yue, Brian Ferslew, Kevin Watt, Jason Slizgi, and Cen Guo. And my special thanks to Nathan Pfeifer, Kathleen Köck and Rhiannon Hardwick for all the times we shared working in the lab day and night, and all the adventures we took outside the lab. All of our undergraduate work-study students who have helped with many experiments and keeping lab space clean and neat, notably: Kevin Harris, Pearl Nguyen, Matthew Sanchez, and Kevin Le. PK/PD and T32 postdoctoral fellows for their insights and helpful suggestions on modeling projects and manuscript preparation: Dora Dumitrescu, Christina Mayer, Mario Sampson, Curtis Johnston, Danny Gonzalez, and Eleftheria Tsakalozou. Arlo Brown and Kathy Maboll who have helped me with important processes and document in the program step by step. I could not have made it without fellow graduate v students of my year, Nicole Zane, Akinyemi Oni-Orisan, and Dan Crona, who were there with me enduring together the coursework and the qualifying exam, and celebrating survival. I also want to thank a number of ESOP members who have helped me throughout the graduate school years: Christina Won, Julie Lauffenburger, Melea Ward, Scott Brantley, Brandon Gufford, Garrett Ainslie, and Kristina Wolf. I cannot thank the DILIsim team and the folks at the Hamner Institutes enough for their support and all the times we spent together; Jeffrey Woodhead, Scott Siler, Yuching Yang, Lisl Shoda, Patti Steele, and Geoffrey Bock. There are so many people who had brought expertise from various fields and help strengthen my research: Alexander Sedykh, Alexander Tropsha, Bob St. Claire, Cassandra Hubert, and Paul Stewart. I also thank my previous advisors and mentors, Myung Gull Lee and Hyunyoung Jeong, who led me to the exciting world of science and have been watching my development ever since. I also need to thank many people whom I met in this home far away from my home in South Korea. Without their personal and emotional support, I could not made it through. “Baity Hill sisters” who had been with me during good times and bad times since I arrived in Chapel Hill: Jane Lim, Gina Song, Sujeong Kim, and Younjee Chung. All the members of Nehemiah at Duraleigh Presbyterian Church and my group members at Bible Study Fellowship for their support and prayer. Denise Dietrich, for our fellowship and the wonderful times we spent together every Monday night. My friends from Chicago who cares and supports me: Kwi Hye Koh, Su-Young Choi, Yeonjoo Lee, and Hyunjoo Lee. I also want to thank my old friends for being there whenever I need encouragement: Sora Park who has known me since I was a little child, and Seojin Huh with whom I spent my exciting years in the Pharmacy School. Finally, and most importantly, my family: my cheering sisters Kyungjin and Kyungjee, who can always make me laugh even during the hard times. I also would like to thank my parents-in-law, Youngki Yang and Sungsook Lee, for their continuing prayer and loving support for me. Mom and Dad, thanks for everything you have done for me – for your nurturing love, support for my dreams, and countless things I cannot even list all. This work is for my beloved husband, Sihyung Yang; I could not have made this journey without your faithful love and support, and look forward to a lifelong journey with you. Lastly, I would like to thank my greatest mentor, friend, and savior: God. I know that you have been with vi me and guiding me during all the paths of my life. I will never forget what a great fortune I have had in being here, and that it comes with a responsibility. I am thankful for your presence and for all the things you allowed and did not allow in my life, and hope I am doing the work you have planned me to do for your good purpose. vii TABLE OF CONTENTS LIST OF TABLES ....................................................................................................................................... ix LIST OF FIGURES ...................................................................................................................................... x CHAPTER 1. Introduction ............................................................................................................................ 1 CHAPTER 2. Analysis of Hepatic Transport Proteins ............................................................................... 53 CHAPTER 3. Species Differences in Hepatobiliary Disposition of Taurocholic acid in Human and Rat Sandwich-Cultured Hepatocytes; Implications for Drug-Induced Liver Injury ............................................................................................... 98 CHAPTER 4. An Experimental Approach to Evaluate the Impact of Impaired Transport Function on Hepatobiliry Drug Disposition using Mrp2-deficient TR- Rat Sandwich-Cultured Hepatocytes in Combination with Bcrp Knockdown................................................ 124 CHAPTER 5. Hepatocellular Exposure of Generated Metabolites, Troglitazone Sulfate and Glucuronide, is Determined by the Interplay between Formation and Excretion in Rat Sandwich-Cultured Hepatocytes Lacking Selected Canalicular Transporters ............................... 153 CHAPTER 6. Quantitative Relationship between Intracellular Lithocholic Acid, Chenodeoxycholic Acid and Toxicity in
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