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Interplay Between Metformin and Serotonin Transport in the Gastrointestinal Tract: a Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin

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Interplay Between Metformin and Serotonin Transport in the Gastrointestinal Tract: a Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin INTERPLAY BETWEEN METFORMIN AND SEROTONIN TRANSPORT IN THE GASTROINTESTINAL TRACT: A NOVEL MECHANISM FOR THE INTESTINAL ABSORPTION AND ADVERSE EFFECTS OF METFORMIN Tianxiang Han 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 2013 Approved By: Dhiren R. Thakker, Ph.D. Michael Jay, Ph.D. Kim L. R. Brouwer, Pharm.D., Ph.D. Joseph W. Polli, Ph.D. Xiao Xiao, Ph.D. © 2013 Tianxiang Han ALL RIGHTS RESERVED ii ABSTRACT TIANXIANG HAN: Interplay between Metformin and Serotonin Transport in the Gastrointestinal Tract: A Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin (Under the direction of Dhiren R. Thakker, Ph.D.) Metformin is a widely prescribed drug for Type II diabetes mellitus. Previous studies have shown that this highly hydrophilic and charged compound traverses predominantly paracellularly across the Caco-2 cell monolayer, a well-established model for human intestinal epithelium. However, oral bioavailability of metformin is significantly higher than that of the paracellular probe, mannitol (~60% vs ~16%). Based on these observations, the Thakker laboratory proposed a “sponge” hypothesis (Proctor et al., 2008) which states that the functional synergy between apical (AP) transporters and paracellular transport enhances the intestinal absorption of metformin. This dissertation work aims to identify AP uptake transporters of metformin, determine their polarized localization, and elucidate their roles in the intestinal absorption and adverse effects of metformin. Chemical inhibition and transporter-knockdown studies revealed that four transporters, namely, organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT), serotonin reuptake transporter (SERT) and choline high-affinity transporter (CHT) contribute to AP uptake of metformin in Caco-2 cells. Although AP intestinal localization of PMAT, SERT and CHT has been established, the intestinal membrane localization of OCT1 is ambiguous in the literature. In this dissertation work, iii functional and immunostaining studies showed that OCT1 is localized in the AP membrane of Caco-2 cells and human and mouse intestinal epithelia. Since this dissertation data showed for the first time that metformin is a substrate of SERT, the in vivo role of this transporter in mediating metformin oral absorption was investigated. The SERT-selective chemical inhibitor, paroxetine, decreased metformin systemic AUC0-6h by 9% (p<0.05), and in mSert-/- mice, metformin systemic AUC0-6h was lowered by 6% (p<0.05). Because SERT mediates the reuptake of serotonin which modulates gastrointestinal (GI) functions, its role in metformin-mediated GI adverse effects, such as diarrhea, was investigated in a mouse model. Results showed that metformin induced a 4-fold increase (p<0.001) in intestinal motility, and a 50% increase (p<0.05) in water content of the large intestine. These effects were diminished by serotonin receptor 4 antagonist GR113808, suggesting that metformin could cause GI adverse effects, such as diarrhea, by inhibiting SERT-mediated serotonin re-uptake and subsequent serotonin-induced increased GI motility and water-retention. iv ACKNOWLEDGEMENTS I am incredibly grateful to my advisor Dr. Dhiren R. Thakker for his support, mentorship, patience, and friendship throughout my graduate training. It is an immense pleasure and honor to have him as my life-time mentor, academic father, and valuable friend. I am deeply indebted to my committee members, Drs. Michael Jay, Kim L. R. Brouwer, Joseph W. Polli, and Xiao Xiao for their time, suggestions, and insights. Their help, advice, and wisdom have deeply inspired me. I consider it a tremendous privilege to have them serve as members of my committee. I would like to express my appreciation to all previous and current members of the Thakker laboratory. Their friendship, support and help have enabled to make the time spent at UNC, both meaningful and joyous. Among them, I would like to especially thank the laboratory members with whom I have had the pleasure of working, including Drs. Ruth Everett, Ming Xin, William Proctor, Claudia Generaux, Matthew Dufek, Ravindra Alluri, Wahajuddin Fariuddin, Innocent Ononiwu, Nicole Zane, and Purav Bhatt, as well as Doctors- to-be, Chester Costales, Hao Cai, Deanna Wung, Erin Damery, and Bryan Mackowiak. I deeply cherish their friendship, and consider them my family in America. I would like to particularly thank Dr. Ruth S. Everett for her incredible support, mentorship, kindness and patience during my graduate training. I would like to acknowledge all the faculty members, students, post-doctoral fellows, and staff at the UNC Eshelman School of Pharmacy for their help and support, which has v made my experience here memorable and rewarding. In particular, I would like to thank Drs. Moo Cho, Leaf Huang, Kim L.R. Brouwer, Roy Hawke, Craig Lee, Angela Kashuba, Mary Paine and members of their laboratories for providing invaluable help and for being so willing to share their equipment. I would like to thank all members of the Michael Hooker Microscopy Facility, Biomedical Research Imaging Center, and Histology Research Core Facility at UNC for their service and help for my dissertation work. I would also like to thank Drs. Timothy M. Farrell and D. Wayne Overby at the Department of Surgery, UNC School of Medicine for their assistance in providing human intestinal tissues for this study. This dissertation work was made possible by generous support by the Pre-doctoral Fellowship from Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (now Janssen Pharmaceuticals, Inc.), and Dissertation Completion Fellowship from the Graduate School of the University of North Carolina at Chapel Hill. This project was funded in part by the National Institutes of Health Grant R01-DK088097. I would like to express my deepest gratitude to my family and friends for helping me through this long journey. In particular, I would like to express my greatest appreciation to my wife Yang Ran, who has given up everything and traveled halfway around the world to be with me, and has loved and supported me unconditionally. Furthermore, I would like express my deepest and sincerest gratitude to my parents, Dr. Longen Han and Shuchun Xia, for their unwavering love, tireless support, and continuous encouragement throughout my life. Additionally, I would like to thank my parents-in-law, Kangming Ran and Qingling Li, for their support, trust and encouragement. vi DEDICATION To my wise parents, for giving me life and inspiring me in science and medicine, To my loving wife, for giving me the reason to continue and prosper. May this work make a difference in people’s lives. vii TABLE OF CONTENTS Page LIST OF TABLES .....................................................................................................................x LIST OF FIGURES ................................................................................................................. xi LIST OF ABBREVIATIONS ................................................................................................ xiv CHAPTERS 1. INTRODUCTION ...............................................................................................................1 A. INTRODUCTION .........................................................................................................1 B. CATION-SELECTIVE TRANSPORTERS ..................................................................3 C. CATION-SELECTIVE TRANSPORTERS IN DRUG-INDUCED TOXICITY IN ORGANS ............................................................................................10 D. CATION-SELECTIVE TRANSPORTERS IN TOXICITY OF THERAPEUTIC AGENTS .........................................................................................14 E. METFORMIN..............................................................................................................19 F. RATIONALE AND OVERVIEW OF PROPOSED RESEARCH .............................27 2. FOUR CATION-SELECTIVE TRANSPORTERS ARE INVOLVED IN THE APICAL UPTAKE AND ACCUMULATION OF METFORMIN IN CACO-2 CELL MONOLAYERS .......................................................54 A. OVERVIEW ................................................................................................................54 B. INTRODUCTION .......................................................................................................56 C. MATERIALS AND METHODS .................................................................................59 D. RESULTS ....................................................................................................................66 viii E. DISCUSSION ..............................................................................................................74 3. ORGANIC CATION TRANSPORTER 1 IS LOCALIZED IN THE APICAL MEMBRANE OF CACO-2 CELL MONOLAYERS AND ENTEROCYTES .....................................................................................................96 A. OVERVIEW ................................................................................................................96 B. INTRODUCTION .......................................................................................................98 C. MATERIALS AND METHODS ...............................................................................101 D. RESULTS ..................................................................................................................109
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