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The Slc22 Transporter Family: Novel Insights to Roles in Drug Efficacy, Drug-Drug Interactions and Mood Disorders

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The Slc22 Transporter Family: Novel Insights to Roles in Drug Efficacy, Drug-Drug Interactions and Mood Disorders Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2015 THE SLC22 TRANSPORTER FAMILY: NOVEL INSIGHTS TO ROLES IN DRUG EFFICACY, DRUG-DRUG INTERACTIONS AND MOOD DISORDERS Xiaolei Pan Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Pharmaceutics and Drug Design Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/3983 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Xiaolei Pan, 2015 All Rights Reserved THE SLC22 TRANSPORTER FAMILY: NOVEL INSIGHTS TO ROLES IN DRUG EFFICACY, DRUG-DRUG INTERACTIONS AND MOOD DISORDERS A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By Xiaolei Pan Master of Science, Shenyang Pharmaceutical University, China, 2011 Director: Douglas H. Sweet, Ph.D. Professor, Interim Chair Department of Pharmaceutics, School of Pharmacy Virginia Commonwealth University Richmond, Virginia, August 3rd, 2015 ii ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor Dr. Douglas H. Sweet for his time, ideas and funding to support my Ph.D. studies. He is one of the smartest advisor I ever know, and the enthusiasm he has for his research was contagious and motivational for me. Dr. Sweet has been supportive and given me the freedom to pursue research with my interest in different topics, and I am grateful for his excellent guidance that help me conquer any challenges these years. I would also like to thank my committee members Drs. Jürgen Venitz, Phillip Gerk, Malgorzata Dukat and Adam VanWert for their consistent help in my research. Dr. Venitz and Dr. Gerk have given me numerous brilliant valuable comments and suggestions in the PK/PD research group, and I have benefited tremendously from those weekly discussions. I also want to thank Dr. Dukat and Kavita Iyer for all the collaborations and suggestions in the quinazolines and guanidines project, and Dr. VanWert as a thesis reader and an inspiration in many ways. A special gratitude I give to Dr. Richard A Glennon for providing and guiding me in the synthetic cathinones project. In addition, many thanks go to all faculties in School of Pharmacy for their help in my coursework. I would also like to thank Ms. Keyetta Tate, Ms. Laura Georgiadis and Ms. Shakim Jackson for their kindly help in arranging departmental activities, lab and office supplies, and paperwork for graduation and reimbursement. I would like to thank my lab-mates Dr. Aditi Mulgaonkar, Dr. Christine A. Farthing, Raymond Lai and Hebing Liu for their help in my study, and all my fellow and senior Pharmaceutics graduate students for their help and advice. In addition, a special thank you to my friends and roommates in Richmond for their support and encouragement. I would thank the VCU School of Pharmacy, Graduate School and Altria Fellowship for the financial support. Lastly, I would like to thank my family for all their love and encouragement. My parents raised me with all their love and supported me in all my pursuits. And most of all for my loving, supportive, encouraging, and patient husband Li Wang whose faithful support through my Ph.D. is so appreciated. Thank you. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS…………………………………………………………………..…ii TABLE OF CONTENTS ………………………………………………………………………iii LIST OF TABLES……………………………………………………………………………...vii LIST OF FIGURES……………………………………………………………………………viii ABBREVIATIONS………………………………………………………………………………x ABSTRACT…………………………………………………………………………………….xiv CHAPTERS 1. THE SLC22 TRANSPORTER FAMILY: NOVEL INSIGHTS TO ROLES IN DRUG EFFICACY, DRUG-DRUG INTERACTIONS AND MOOD DISORDERS …………….....1 1.A OVERVIEW OF ORGANIC CATION AND ANION TRANSPORTERS ……....…1 1.B EXPRESSION OF ORGANIC CATION AND ANION TRANSPORTERS IN BRAIN …………………………………………………….……………….…………….6 1.C CURRENT EVIDENCE ON ORGANIC CATION TRANSPORTER-MEDIATED NEUROTRANSMITTER DISPOSTION IN BRAIN ………………………..……...21 1.D ORGANIC CATION AND ANION TRANSPORTER-MEDIATED DRUG INTERACTION …………………………………………….…………………..……..25 2. RESEARCH OBJECTIVES AND SPECIFIC AIMS………..……………………………28 2.A RESEARCH OBJECTIVES …..…………………………………………………...…28 2.B SPECIFIC AIMS TO ADDRESS THE ABOVE HYPOTHESES…………….……29 3. THE ANTHRAQUINONE DRUG RHEIN POTENTLY INTERFERES WITH ORGANIC ANION TRANSPORTER-MEDIATED RENAL ELIMINATION ...……….. 30 iv 3.A INTRODUCTION…………………………………………………………..………….30 3.B MATERIALS AND METHODS……………………………………………….……..33 3.B.1 Chemicals ……………………………………………………………..………….33 3.B.2 Tissue culture …………………………………………………………….………33 3.B.3 Cellular uptake assay ………………………………..……………………..…….34 3.B.4 Statistics ……………………………………………………….…………………34 3.C RESULTS………………………………...…………….…………………………………..35 3.C.1 Inhibitory effects of rhein on hOAT1-, hOAT3-, and hOAT4-mediated substrate uptake …………………………………………………………………………….35 3.C.2 Inhibitory effects of rhein on mOat1- and mOat3-mediated substrate uptake …...39 3.D DISCUSSION……………………..……………………………………….……………… 42 4. INTERACTION OF ETHAMBUTOL WITH HUMAN ORGANIC CATION TRANSPORTERS (SLC22 FAMILY) INDICATES POTENTIAL FOR DRUG-DRUG INTERACTIONS DURING ANTITUBERCULOSIS THERAPY ………………………...47 4.A INTRODUCTION………………………………………………………….….……….47 4.B MATERIALS AND METHODS……………………………………………………...49 4.B.1 Chemicals……………….………………………………………………..……… 49 4.B.2 Tissue culture……………………………………………………...……………...50 4.B.3 Cell accumulation assays………………………………………………...……….51 4.B.4 Statistics Drug-drug interaction (DDI) index calculation ……………………......52 4.B.5 Statistical analysis ……………………………………………………...………...53 4.C RESULTS…………………………………………………………………………….…55 4.C.1 Inhibitory effects of EMB on hOCT1-, hOCT2-, and hOCT3-mediated MPP+ uptake …………………………………………………………………………….55 4.C.2 Inhibitory effects of EDA on hOAT (hOAT1andhOAT3) and hOCT (hOCT1, hOCT2, and hOCT3) transport activity ……………….…………………………59 4.D DISCUSSION………………………………………………………………………...…61 v 5. INHIBITION OF HUMAN ORGANIC CATION TRANSPORTERS BY THE ALKALOIDS MATRINE AND OXYMATRINE……...…………………………………… 65 5.A INTRODUCTION……………………………………………………………….…...…65 5.B MATERIALS AND METHODS…………………………………………..……..……67 5.B.1 Chemicals………………………………………………………...……………… 67 5.B.2 Tissue culture………………………………..……………………………...…….68 5.B.3 Cell accumulation assay………………………………………...…...……………68 5.B.4 Statistical analysis ……………………………………………...…………….…..69 5.C RESULTS……………...………………………………………………………………..69 5.C.1 Inhibitory effects of matrine and oxymatrine on hOCT1-mediated MPP+ uptake ………………………………………………………………………..….. 69 5.C.2 Inhibitory effects of matrine and oxymatrine on hOCT2-mediated MPP+ uptake …………………………………………………………………….……....71 5.C.3 Inhibitory effects of matrine and oxymatrine on hOCT3-mediated MPP+ uptake ………………………….………………………….……………………. 71 5.D DISCUSSION…………..………………………………………………………………74 6. INHIBITION OF HUMAN ORGANIC CATION TRANSPORTERS BY THE SYNTHETIC CATHINONE ANALOGS (“BATH SALTS”)…….………………………...77 6.A INTRODUCTION………………………………………………………………………77 6.B METHODS…………………………………...………………..………………………..80 6.B.1 Chemicals ………………………………..……………...……………………….80 6.B.2 Tissue culture ……………………………………………………….……………82 6.B.3 Cell accumulation assays………………………………………….…………….. 82 6.B.4 Statistics……………………………………………………….………………… 83 6.C RESULTS……………………………………………………………………..………...83 6.C.1 Inhibitory effects of synthetic cathinones on hOCT1-mediated MPP+ uptake …..83 6.C.2 Inhibitory effects of synthetic cathinones on hOCT2-mediated MPP+ uptake ..…86 vi 6.C.3 Inhibitory effects of synthetic cathinones on hOCT3-mediated MPP+ uptake ..…88 6.D DISCUSSION…………………………………………………………………..…….....91 7. THERAPEUTIC POTENTIAL OF NOVEL ORGANIC CATION TRANSPORTER (OCT; SLC22 FAMILY) INHIBITORS IN DEPRESSION ………………………....……...95 7.A INTRODUCTION……………………………………………………………...……… 95 7.B MATERIAL AND METHODS……………………………………………...…………97 7.B.1 Chemicals …………..………………………………………..…………..……… 97 7.B.2 Tissue Culture .……………………………………………………..…………….99 7.B.3 Cell accumulation assays …..…………………………………………….………99 7.B.4 Mode of inhibition for lead compounds ..……………………………………… 100 7.B.5 Mouse behavior assessment …………..………………………………...………101 7.B.6 hOCT3 homology modeling and docking studies …………………………..… .102 7.C RESULTS AND DISCUSSION………………………………………………………102 7.C.1 Initial screening of quinazolines and guanidines as OCT inhibitors ….…...……102 7.C.2 Determination of IC50 values for quinazolines and guanidines …………………104 7.C.3 Inhibition potencies of KEO-099 for hOCT2-mediated 5-HT uptake ..…...…... 115 7.C.4 Mode of inhibition for hOCT2 and hOCT3 ………………………...…...…...…118 7.C.5 Mouse behavior studies ……………………...……..…………………..………119 7.C.6 Homology modeling and docking studies for hOCT3……….……...…………..121 7.D DISCUSSION ……………………………………………………..……….………...125 8. OVERALL CONCLUSIONS AND FUTURE DIRECTIONS………………...………..130 REFERENCES……………………………………………………..…………………………139 VITA……………………………………………………………………….…………………. 154 vii LIST OF TABLES Table 1.1 Expression of OCTs/Octs in choroid plexuses …………………………...12 Table 1.2 Expression of OCTs/Octs in blood brain barrier …………………………13 Table 1.3 Expression of OCTs/Octs in neuron and glia cells ……………………….15 Table 1.4 Expression of OCTs/Octs in different brain regions ……………………..16 Table 3.1 Estimated kinetic constants (IC50, Ki) and DDI indices for rhein on OATs ………………………………………………………………….....42 Table 4.1 Estimated DDI index values for EMB on hOCT-mediated transport after an oral dose
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