A PREDICTIVE MULTISCALE MODEL of DRUG TRANSPORT By
Total Page：16
File Type：pdf, Size：1020Kb
FROM CELL TO ORGANISM: A PREDICTIVE MULTISCALE MODEL OF DRUG TRANSPORT by Xinyuan Zhang A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmaceutical Sciences) in The University of Michigan 2010 Doctoral Committee: Associate Professor Gustavo Rosania, Chair Professor Gordon L. Amidon Professor Steven P. Schwendeman Professor Shuichi Takayama © Xinyuan Zhang 2010 To my parents and my husband With all my love and thanks ii ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. Gus R. Rosania, for all of his insightful and valuable guidance during my Ph.D. study. I learned not only scientific knowledge from him, but also the way and attitude of doing science, being honest, creative, and open. His office door is always open and whenever I had questions, I always felt free to go and ask. I am grateful for his continuous support to many decisions I made, such as pursuing Master’s degree in Statistics, doing an internship in my last year of study, and attending many conferences to present my work. I would also like to thank my dissertation committee members, Dr. Gordon L. Amidon, Dr. Steven P. Schwendeman, and Dr. Shuichi Takayama, for their valuable time, suggestions, and input. All the unexpected questions, challenges, discussions, and suggestions made me think further and more deeply about my project. I would like to thank Dr. Stefan Trapp from the Technical University of Denmark and Dr. Richard W. Horobin from the University of Glasgow, for their help with the original model. I thank Dr. Kerby Shedden from the Department of Statistics of the University of Michigan, for all the discussions about my project. From him I learned how the statistics can help in scientific discovery. I appreciated the opportunity of studying population pharmacokinetics from Dr. Rose Feng. Discussions with her and suggestions from her helped me a lot when I was extending cell-based pharmacokinetic models to whole body physiologically-based pharmacokinetic models. iii I also received many help from friends, peer students, and alumni of the College of Pharmacy. I would especially like to thank Nan Zheng, Jingyu Jerry Yu, Peng Zou, Jason Baik, Kyoung-Ah Min, Dr. Vivien Chen Nielsen, Maria Posada, Samuel Reinhold, Dr. Jenny Jie Sheng, Dr. Li Zhang, Tien-Yi Lee, Haili Ping, Ke Ma, Hee-Sun Chung, Dr. Theresa Nguyen, and Dr. Yasuhiro Tsume for their friendship and support. I am indebted to the staff of the College of Pharmacy for all their help, with special thanks to Lynn Alexander, Terri Azar, Pat Greeley, L.D. Hieber, Dr. Cherie Dotson, Jeanne Getty, and Maria Herbel. I feel very sorry that Lynn left us forever. I acknowledge all the financial support for my research from the College of Pharmacy, Fred Lyons Jr. Fellowship, and Schering-Plough Graduate Fellowship. Lastly, I want to thank my parents for their love, support and patience; my husband, Zhijiang He, for encouraging me, supporting me, and always being my Matlab consultant. iv TABLE OF CONTENTS DEDICATION .................................................................................................................. ii ACKNOWLEDGEMENTS ............................................................................................ iii LIST OF TABLES .......................................................................................................... vii LIST OF FIGURES ....................................................................................................... viii LIST OF APPENDICES ................................................................................................. xi CHAPTER I .......................................................................................................................1 INTRODUCTION.....................................................................................................1 Abstract............................................................................................1 Introduction......................................................................................3 Subcellular compartment --- How do you define it? .......................4 pH-partition theory and ion-trapping mechanism............................5 The Goldman-Hodgkin-Katz equation ............................................7 Empirical and semi-empirical models .............................................8 Mechanistic physiologically-based models ...................................14 Comparison of empirical models with mechanistic models ..........19 Cellular pharmacokinetics modeling in relation to macroscopic ADMET ..............................................................22 Conclusions....................................................................................23 Specific aims..................................................................................24 References......................................................................................29 CHAPTER II....................................................................................................................39 A CELL-BASED MOLECULAR TRANSPORT SIMULATOR FOR PHARMACOKINETIC PREDICTION AND CHEMINFORMATIC EXPLORATION.................................................39 Abstract..........................................................................................39 Introduction....................................................................................41 Methods..........................................................................................43 Results............................................................................................51 Discussion......................................................................................59 References......................................................................................75 CHAPTER III ..................................................................................................................80 v SIMULATION-BASED CHEMINFORMATIC ANALYSIS OF ORGANELLE-TARGETED MOLECULES: LYSOSOMOTROPIC MONOBASIC AMINES.....................................80 Abstract..........................................................................................80 Introduction....................................................................................82 Methods..........................................................................................84 Results............................................................................................91 Discussion......................................................................................98 References....................................................................................118 CHAPTER IV.................................................................................................................123 CELLS ON PORES: A SIMULATION-DRIVEN ANALYSIS OF TRANSCELLULAR SMALL MOLECULE TRANSPORT ...............123 Abstract........................................................................................123 Introduction..................................................................................125 Materials and Methods.................................................................126 Results..........................................................................................136 Discussion....................................................................................143 References....................................................................................159 CHAPTER V ..................................................................................................................161 SINGLE-CELL PHYSIOLOGICALLY-BASED PHARMACOKINETIC (1CELLPBPK) MODELING OF DRUG DISTRIBUTION IN THE LUNG...............................................161 Abstract........................................................................................161 Introduction..................................................................................163 Methods........................................................................................165 Results..........................................................................................172 Conclusion and Discussion..........................................................174 References....................................................................................185 CHAPTER VI.................................................................................................................189 FINAL DISCUSSION...........................................................................................189 Integration of molecular size .......................................................190 Integration of molecular interactions...........................................190 Mechanistic models for hypothesis testing and experimental design .....................................................................................191 Extension of 1CellPK towards multiorgan PBPK modeling .......192 Disseminating 1CellPK................................................................193 References....................................................................................195 APPENDICES................................................................................................................197 vi LIST OF TABLES Table 1.1: Summary of empirical models for subcellular localization prediction............ 27 Table 1.2: Summary of mechanistic cellular PK models.................................................. 28 Table 2.1.