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Bupropion's Bioinequivalence

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Bupropion's Bioinequivalence Bupropion’s Bioinequivalence: Patient Variability, Absorption, and Metabolism by Jamie Nicole Connarn A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmaceutical Sciences) in the University of Michigan 2015 Doctoral Committee: Professor Duxin Sun, Chair Professor Gordon L. Amidon Professor Vicki L. Ellingrod Professor David E. Smith ©Jamie N. Connarn 2015 Dedication To my family for all their love, prayers, and support; especially my Mom. ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Duxin Sun for all the remarkable opportunities that he gave me during my graduate career as well as the full support and training. Without all his support, knowledge, and dedication to producing successful graduate students, this would not be possible. I would like to thank my committee members; Dr. David Smith, Dr. Gordon Amidon, and Dr. Vicki Ellingrod for all their insightful expertise in guiding my research smoothly. I would also like to thank Dr. Jason Gestwicki, who was a huge help on my Heat Shock Protein studies. In addition, I would like to thank Dr. Rose Feng, Dr. Simon Zhou, and Dr. Yan Li for collaborative projects and all the assistances with my PK analysis. I am grateful for all my lab mates and staff; Hayley Paholak, Joe Burnett, Becky Reed, Xiaoqing Ren, Kanokwan Sansanaphongpricha, Albert Lin, Mari Gasparyan, Alex Yu, Ila Myers, Nathan Truchan, Huixia Luo, Dr. Hongwei Chen, Dr. Ruijuan Luo, Dr. Ting Zhao, Dr. Bo Wen, Dr. Siwei Li, Dr. Xiaoqin Li, Dr. Yasuhiro Tsume, Marisa Gies, and Gail Benninghoff. In addition, I would like to thank those who were a part of our large clinical team; Marisa Kelly, Gloria Harrington, Stephanie Flowers, Kirsten Weiss, Xinyuan (Susie) Zhang, and Andrew Babiskin I would like to express how grateful I am for all of my friends I have met here; Xiaomei Chen, Amy Doty, Morgan Giles, Kelly Hansen, Eric Lachacz, Maya Lipert, Max Mazzara, Allison Maytas, Max Stefan, Charlie Steffens, Arjang Talattof, Karthik Pisupati, Maria Posada, and too many more. I will always remember our great times iii together in Ann Arbor. A special thanks to two of my best friends who helped me through many times over years; Melissa Benham and Maryann Oram. Finally, I would like to thank all of my family especially; my parents Leslie Persin and Jim Connarn and my sister Jennifer and Jessica Connarn for their love and support. iv TABLE OF CONTENTS Dedication ........................................................................................................................ii Acknowledgements ......................................................................................................... iii List of Figures ..................................................................................................................vi List of Appendices ...........................................................................................................ix List of Abbreviations ........................................................................................................ x Abstract .......................................................................................................................... xii Chapter 1 Background and Introduction ......................................................................... 1 Chapter 2 Metabolism of Bupropion by Carbonyl Reductases in Liver and Intestine ... 22 Chapter 3 Method Development, Validation, and Sample Analysis of Bupropion in Human Plasma. ............................................................................................................. 60 Chapter 4 Investigate Different Release Mechanisms that May Alter Absorption, Metabolism, and Pharmacogenomics of Bupropion. ..................................................... 81 Chapter 5 Conclusions ............................................................................................... 108 Appendices .............................................................................................................. 113 v List of Figures Figure 1-1. Subcellular Fractions. ............................................................................... 20 Figure 1-2. Generics Failed BE Standards. ................................................................ 21 Figure 2-1. Bupropion and Metabolism. ....................................................................... 48 Figure 2-2. Method Development for Bupropion and Metabolites.. .............................. 49 Figure 2-3. Hydroxybupropion Metabolite Formation in Liver Subcellular Fractions. ... 50 Figure 2-4. Threohydrobupropion Metabolite Formation in Liver Subcellular Fractions. ...................................................................................................................................... 51 Figure 2-5. Erythrohydrobupropion Metabolite Formation in Liver Subcellular Fractions.. ...................................................................................................................................... 52 Figure 2-6. Threohydrobupropion Metabolite Formation in Intestinal Subcellular Fractions.. .................................................................................................................. 53 Figure 2-7. Threohydrobupropion Metabolite Formation in Intestinal Subcellular Fractions.. ..................................................................................................................... 54 Figure 2-8. Enzyme Expression in Human Subcellular Fractions. ............................... 55 Supplemental Figure 2-1.Hepatocytes Kinetics. .......................................................... 58 Figure 3-1. MRM Chromatograms of Blank Plasma Samples for Selectivity.. .............. 71 Figure 3-2. MRM Chromatograms of Blank Samples with IS for Selectivity.. ............... 72 Figure 3-3. Specificity for Bupropion and Metabolites. .................................................. 73 Figure 3-4. Short term stability. .................................................................................. 79 Figure 3-5. Carryover. ............................................................................................... 80 Figure 4-1. Time vs Concentration Plots. .................................................................... 98 Figure 4-2. Relative Bioavailability. .............................................................................. 99 Figure 4-3. Analysis of Metabolites .. ......................................................................... 100 Figure 4-4. Pharmacogenomics of CYP2B6. ........................................................... 101 Figure 4-5. Weibull Absorption Rate........................................................................... 102 Figure 4-6. Cumulative Percent Absorbed.. ................................................................ 103 Appendix Figure 1-1. HSP90 Complex. 130 Appendix Figure 2-1. SRL-PFAC confirm that both Hsp70-PP5 and Hsp90-PP5 interact. ....................................................................................................................... 155 Appendix Figure 2-2. Fluorescence polarization confirms that Hsp90-PP5 has higher affinity than Hsp70-PP5.. ............................................................................................. 156 Appendix Figure 2-3. Competition studies confirm binding data.. .............................. 157 Appendix Figure 2-4. Hsp70-PP5 and Hsp90 interact with different stoichemetries.. 158 Appendix Figure 2-5. C-terminal residues of Hsc70 bind PP5.. ................................. 159 Appendix Figure 2-6. Hsp70 preferentially stimulates PP5’s phosphatase activity.. .. 160 vi Appendix Figure 3-1. Fluorescence Polarization Assay.. ........................................... 177 Appendix Figure 3-2. Primary Screen of TPR containing proteins-Hsp90 peptide. .... 178 Appendix Figure 3-3. Dose Response Curves from Hit Compounds. ........................ 179 Appendix Figure 3-4. Hits from DRC.. ......................................................................... 180 Appendix Figure 3-5. Suramin inhibits TPR containing proteins-Hsp90. .................. 181 Appendix Figure 3-6. Sumarin and Analogs for inhibiting Hsp90-TPR containing proteins.. ..................................................................................................................... 182 vii List of Tables Table 2-1. Summary of Subcellular Kinetics.. 56 Table 2-2. Estimated Intrinsic Clearance.. .................................................................... 57 Supplemental Table ‎2-1. Hepatocytes Kinetics Summary...................................... ...... 59 Table 3-1. MRM Parameters. .................................................................................... 70 Table 3-2. Standard Curves for Bupropion and Metabolites.. ....................................... 74 Table 3-3. Matrix Effect Analysis. .............................................................................. 75 Table 3-4. Accuracy. ................................................................................................. 76 Table 3-5. Precision. .................................................................................................. 77 Table 3-6. Recovery. ................................................................................................. 78 Table 4-1. Area Under the Curve.. ............................................................................. 104 Table 4-2. Percent of Relative Bioavailability.
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