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The Role of Abcg2 in Drug Active Transport in Milk University of Kentucky UKnowledge University of Kentucky Doctoral Dissertations Graduate School 2010 THE ROLE OF ABCG2 IN DRUG ACTIVE TRANSPORT IN MILK Lipeng Wang University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Wang, Lipeng, "THE ROLE OF ABCG2 IN DRUG ACTIVE TRANSPORT IN MILK" (2010). University of Kentucky Doctoral Dissertations. 59. https://uknowledge.uky.edu/gradschool_diss/59 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Lipeng Wang The Graduate School University of Kentucky 2010 THE ROLE OF ABCG2 IN DRUG ACTIVE TRANSPORT INTO MILK ABSTRACT OF DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Lipeng Wang Lexington, Kentucky Director: Patrick J. McNamara, Ph.D., Professor of Pharmaceutical Sciences Lexington, Kentucky 2010 Copyright © Lipeng Wang 2010 ABSTRACT OF DISSERTATION THE ROLE OF ABCG2 IN DRUG ACTIVE TRANSPORT INTO MILK Drug active transport into milk is a major concern for breastfeeding mothers and healthcare providers. Studies from the literature indicated that breast cancer resistance protein (ABCG2) plays an important role in drug transfer into milk. There has been limited study on stereoselective interactions with ABCG2. A mechanistic analysis of flux across cell monolayer model is a critical first step toward extrapolating in vitro results for predicting in vivo disposition (including distribution into milk), drug disposition or drug- drug interactions. The objectives of this thesis were (1) to establish a “Chemical knockout model” in rat for studying drug accumulation into milk, (2) to investigate the impact of stereoselective interaction between ABCG2/Abcg2 and pantoprazole on drug transport in milk, (3) to understand in vitro monolayer flux model using experimental data and a mechanistic mathematical model. Quantitive PCR, Western blotting and immunohistochemistry results indicated that Abcg2 was up-regulated during lactation and localized on apical side of epithelial cells in mammary gland. In vitro and in vivo experiments confirmed that Abcg2 is responsible for nitrofurantoin active transport in rat milk and GF120918 was established as a chemical knockout model. Abcg2 interacts stereoselectively with pantoprazole isomers. A significant different apical flux between two pantoprazole isomers was observed in Abcg2-MDCKII cell line. The milk to serum (M/S) ratio of (-)-pantoprazole was almost 3 times as that of (+)- pantoprazole in lactating rats. Administration GF120918 decreased M/S of (-)- pantoprazole (p<0.001) but not (+)-pantoprazole (p>0.05). A stably transfected ABCG2/Abcg2 overexpressing MDCKII cell line was successfully created and used to explore the theoretical relationships in a monolayer flux model. Based on the profiles of pantoprazole isomer transport, a simple three compartment model for drug transfer into breast milk incorporating the permeability- surface area products for passive diffusion (PSD), paracellular flux (PSPC) and apically efflux ABCG2 (PSA,E) transfection was developed. The mathematical model was developed to more fully understand the interplay of paracellular, passive diffusion, active transport, and flux kinetic parameters (Km, Vmax, IC50 and Ki). This model provided useful insights into the meaning and limitation of parameters obtained from monolayer flux. KEYWORDS: ABCG2, transporter, chirality, transwell model, lactation, mathematical modeling. Lipeng Wang 10-12-10 Date THE ROLE OF ABCG2 IN DRUG ACTIVE TRANSPORT IN MILK By Lipeng Wang Patrick J. McNamara, Ph.D. Director of Dissertation Jim Pauly, Ph. D Director of Graduate Studies 10-12-10 Date RULES FOR THE USE OF DISSERTATIONS Unpublished dissertations submitted for the Doctor's degree and deposited in the University of Kentucky Library are as a rule open for inspection, but are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but quotations or summaries of parts may be published only with the permission of the author, and with the usual scholarly acknowledgments. Extensive copying or publication of the dissertation in whole or in part also requires the consent of the Dean of the Graduate School of the University of Kentucky. A library that borrows this dissertation for use by its patrons is expected to secure the signature of each user. Name Date DISSERTATION Lipeng Wang The Graduate School University of Kentucky 2010 THE ROLE OF ABCG2 IN DRUG ACTIVE TRANSPORT IN MILK DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Lipeng Wang Lexington, Kentucky Director: Patrick J. McNamara, Ph.D., Professor of Pharmaceutical Sciences Lexington, Kentucky 2010 Copyright © Lipeng Wang 2010 DEDICATION With deepest appreciation, this dissertation is dedicated to my husband and my parents for their love and support over the years. ACKNOWLEDGEMENTS This dissertation contains many years of not only my own effort on study and work but also support and encouragement from many generous and inspiring people. Without their support this dissertation would not have been completed. First and foremost, I thank my mentor, Dr. Patrick J. McNamara for providing this wonderful opportunity for me to develop a scientist. He devoted an inordinate amount of time guiding me through the challenges in my graduate student life. He is a thoughtful research scientist who has deep insight to discover the theory under the surface of experiment results. He always could see the problems and difficulties in my study and research where I was experiencing even sometimes I did not really realize them. He was always there to listen and to give guidance, encouragement and help in both my research career and personal life whenever how busy he was. The almost 5 years graduate student life that I have worked with him has been fun, rewarding, interesting and challenging, and along the way I am getting mature as a scientist. I will always appreciate for his education, advice, patience and help. His passion, dedication and diligence towards the work made the best example for me to follow in my future career. I also acknowledge the contributions of each of my committee members Drs. Mary Vore, Peter Wedlund and Markos Leggas. Their advice, discussions and challenging, thoughtful questions helped me to achieve a nice PhD research. I would like to thank Dr. Arthur Cammers as my outside examiner for his time and attention. I also would like to thank Drs. Paul Bummer and Brad Anderson for their suggestion and help. I am appreciative for several previous students in Dr. McNamara’s lab: Phillip Empey, Maggie Abbassi, Phillip Gerk and Jane Alcorn for sharing experiment methods and giving help on my work. Collaboration played a key role in the success of this project. I would like to thank colleagues in Dr. Leggas’s lab, Mamta Goswami for her assistance of ABCG2 transfection in MDCKII cell line and Sf9 cell line, Jamie Horn for helping me to solve the HPLC problems, Kuei-ling Kuo for the research experience which we have been through together and Elefthefia for her time spending on LC-MS method development in lab rotation. I would also express my specially appreciation to Catina Rossoll for assisting me with the administrative tasks for completing my doctoral program. I appreciate the assistance of Dr. Jennifer Strange and Dr. Greg Bauman at the Flow Cytometry Core Facility, John May at ERTL center. Then, I would like to i acknowledge the financial support of the Graduate School and the Department of Pharmaceutical Sciences, American Association of Pharmaceutical Science for the travel support to the meetings to present my work. Last but not least, I would like to thank my parents, Shumei Zai and Shengtai Wang for raising me up and always encouraging me to pursue the knowledge, my husband, Chengjun Huo for his love, patience and support. They gave me the courage and strength to overcome the difficulties over the years. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ................................................................................................. i TABLE OF CONTENTS ................................................................................................. iii CHAPTER 1: Introduction ................................................................................................ 1 A. The benefit of breastfeeding and breastfeeding trends in the United States ......................................................................................................................... 1 B. Drug use during breastfeeding .................................................................................... 3 C. Physiological mechanisms of drug transfer into milk ................................................... 6 1. Physiology of mammary gland ......................................................................... 6 2. Milk components and secretion pathways ....................................................... 7 D. The pathway of drug transfer into milk .....................................................................
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