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OPTIMIZATION of AMIFOSTINE ADMINISTRATION for RADIOPROTECTION by Zheng Lu a Dissertation Submitted in Partial Fulfillment Of

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OPTIMIZATION of AMIFOSTINE ADMINISTRATION for RADIOPROTECTION by Zheng Lu a Dissertation Submitted in Partial Fulfillment Of OPTIMIZATION OF AMIFOSTINE ADMINISTRATION FOR RADIOPROTECTION by Zheng Lu A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmaceutical Sciences) in The Univeristy of Michigan 2007 Doctoral Committee: Professor David E. Smith, Chair Professor Gordon L. Amidon Professor Theodore S. Lawrence Adjunct Associate Professor Meihua Rose Feng Research Associate Professor Daniel P. Normolle © Zheng Lu All rights reserved 2007 DEDICATION To my grandma Kunhou Tian (田坤厚) My uncle jicang zhuo （卓济苍） My wife Yan Cai （蔡燕） and son Victor Lu（卢安博） For their true love ii ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. David Smith, for his guidance, patience and support during my graduate studies in the Department of Pharmaceutics of the University of Michigan. I appreciate his acceptance of me into his lab as his Ph.D. student when I transferred from University of Minnesota, providing this excellent research opportunity and project for me in the field of pharmaceutical sciences. I have been studying and working in his lab for five years of my life, and I am feeling his lab is my second home, his insightful and instructional advice on my acedemica and my life make me really feel lucky to be a member of his group family. I am very thankful to Drs. Gordon Amidon, Daniel Normolle, Theodore Lawrence and Rose Feng for serving on my research committee. It was a great pleasure and unique experience to work and interact with these excellent scientists. I must thank Dr. Normolle for his extraordinary effort during my thesis research and his scientific expertises triggered my strong interest in knowing and learning SAS programming and application of it to the field of pharmacokinetics and further advanced statistical study. I appreciate Dr. Rose Feng’s guidance, discussion and help during my later phase of my Ph.D. study, she is another great tutor who led me into the world of population pharmacokinetics and NONMEM programming. I also wish to thank Dr. Gordon Amidon for his scientific guidance and advice in my research work and Dr. Theodore Lawrence who is the iii principal investigator of the project I have been working for his patience and kindness to offer me this challenging research opportunity to continue my training. I also acknowledge great help and time from Dr. Thomas Ludden from Globomax, Dr. Jack Cook, Dr. Matt Hutmacher, Dr. Daniele Ouellet, Dr. Sunny Chapel and Bill Frame from Pfizer, they probably won’t see this and don’t remember their help to me because most help is by emails, however, I will remember their help forever because they are really helpful at that point. My gratitude extends to the faculty, staff and students at the Department of Pharmaceutical Sciences, University of Michigan, for their friendship, support and help during my stay here, especially our current group members Yongjun, Dilara, Ke, Mohamed, Huidi and Jenney Jie Sheng. Finally, I am greatly indebted to my parents for their love, patience, support and encouragement. The greatest thanks go to my wife and my uncle for their great help to me, also my grandmother and grandfather living in my heart forever for being the source of inspiration and my spirital support when I face difficulties in my life. iv TABLE OF CONTENTS DEDICATION.................................................................................................................... ii ACKNOWLEDGEMENTS............................................................................................... iii LIST OF TABLES...............................................................................................................x LIST OF FIGURES .......................................................................................................... xii LIST OF APPENDICES.................................................................................................. xiv ABSTRACT.......................................................................................................................xv CHAPTER 1. RESEARCH OBJECTIVES ..........................................................................................1 2. BACKGROUND AND LITERATURE REVIEW .......................................................7 2.1 Problems and solutions of intrahepatic cancer treatmen.........................................7 2.1.1 Anatomy and physiology of the liver.......................................................10 2.1.2 Liver pathophysiology with radiotherapy................................................11 2.2 Cytoprotectants against chemo- and radiotherapy induced cytotoxicity .............12 2.2.1 Cytoprotectants ........................................................................................11 2.2.2 Chemistry of amifostine...........................................................................15 2.2.3 Detection of amifostine and WR-1065 ....................................................17 2.3 Pharmacodynamic properties of amifostine.........................................................19 2.3.1 Mechanism of action................................................................................19 2.3.2 Protection against cytotoxic chemotherapy ..............................................22 v 2.3.3 Protection against radiotherapy..................................................................24 2.4 Pharmacokinetic properties of amifostine .............................................................27 2.4.1 Absorption..................................................................................................27 2.4.2 Distribution ................................................................................................30 2.4.3 Elimination.................................................................................................32 2.4.4 Drug interaction .........................................................................................35 References....................................................................................................................40 3. DETERMINATION OF AMIFOSTINE AND WR-1065 IN BLOOD/PLASMA AND TISSUE SAMPLES BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPH COUPLED WITH ELECTROCHEMICAL DETECTOR..........................................47 Abstract................................................................................................................47 Introduction..........................................................................................................49 Materials and Methods.........................................................................................51 3.1 Chemicals and reagents………………………………………………51 3.2 Sample processing ...............................................................................51 3.2.1 Amifostine in plasma by amperometric detector......................51 3.2.2 WR-1065 in whole blood by amperometric detector................51 3.2.3 WR-1065 in tissue by amperometric detector ..........................52 3.2.4 WR-1065 in whole blood by coulometric detector...................52 3.3 Instrumentation ....................................................................................52 3.2.1 Amifostine in plasma by amperometric detector......................52 3.2.2 WR-1065 in whole blood by amperometric detector................53 3.2.3 WR-1065 in tissue by amperometric detector ..........................53 vi 3.2.4 WR-1065 in whole blood by coulometric detector...................54 3.4 Calibration standards and quality controls...........................................55 3.4.1 Standard solutions.....................................................................55 3.4.2 Quality control and assay validation.........................................56 Results..................................................................................................................56 Chromatography ........................................................................................56 Assay validation.........................................................................................57 Discussion............................................................................................................58 References............................................................................................................72 4. RELATIONSHIP BETWEEN AMIFOSTINE DOSE, ADMINISTRATION ROUTE (SYSTEMIC VS REGIONAL), AND SAMPLING TIME ON WR-1065 EXPOSURE IN THE LIVER OF TUMOR-BEARING RATS ..................................73 Abstract................................................................................................................73 Introduction..........................................................................................................75 Materials and Methods.........................................................................................78 4.1 Animals................................................................................................78 4.2 Tumor implantation .............................................................................78 4.3 Experimental protocol..........................................................................78 4.4 Assay for WR-1065 .............................................................................80 4.4.1 Sample preparation ...................................................................80 4.4.2 HPLC analysis ..........................................................................80 4.5 Statistics ...............................................................................................81
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