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Characterization of Influx Transporters in the Blood-Brain Barrier: Implications for Drug Delivery

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Characterization of Influx Transporters in the Blood-Brain Barrier: Implications for Drug Delivery Characterization of Influx Transporters in the Blood-Brain Barrier: Implications for Drug Delivery by Lawrence Lin DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pharrnaeogenorrucs in the ii ACKNOWLEDGEMENTS The text of Chapter 2 is a modified version of the material as it appears in Nature Reviews Drug Discovery. LL, SWY, RBK and KMG researched data and wrote the manuscript. The text of Chapter 6 is a modified version of the material as it appears in Journal of Pharmacokinetics and Pharmacodynamics. SWY, LL, MM and MJK participated in the design and execution of the study and performed the analyses. AG, YZ and HCC participated in the execution of the study. SWY, LL and MJK wrote the manuscript. BKS and KMG participated in the study design, data analysis and manuscript preparation. iii ABSTRACT Characterization of Influx Transporters in the Blood-Brain Barrier: Implications for Drug Delivery Lawrence Lin Membrane transport proteins of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies have been found to play essential roles in the absorption, distribution and elimination of drugs. However, much of the pharmacologic research on transporters has focused primarily on the intestine, liver and kidney. Here we focus on transporters in the blood-brain barrier (BBB), a complex barrier that limits penetration of most molecules from the blood into the brain. Research on transporters in the BBB has historically been centered on the ABC transporters that prevent drug entry into the brain, but recent advances suggest that SLC transporters may play an important role in mediating the uptake of many pharmacologic agents into the central nervous system (CNS). The goal of this dissertation research was to understand the role and function of several SLC transporters in the BBB, including the amino acid transporter LAT1, the organic cation transporter MATE1, the amine transporters OCT1, OCT3 and SERT, and the organic anion transporters OATP1A2 and OATP2B1. We performed inhibition and substrate screens using stably-transfected cell lines against a library of CNS-active drugs. We were able to identify four novel, structurally-diverse inhibitors of LAT1 and developed a rat perfusion model to test LAT1 substrates for in vivo relevance. For MATE1, we found that the majority of compounds tested from our library were inhibitors of MATE1, and identified 15 novel substrates, suggesting that MATE1 may be involved in the disposition of these drugs. Since organic anion transporting polypeptides are known to play a role in the influx iv of molecules into the brain, we performed substrate screens and identified 24 novel substrates of OATP1A2, most of which are cationic drugs. About one-third of the OATP1A2 substrates were also substrates of its rodent ortholog, rat Oatp2. Finally, we found that at high concentrations, metformin is able to inhibit the uptake of two CNS active monoamines, histamine and serotonin, by OCT1, OCT3 and SERT. Though further studies are clearly needed, we posit that reduced absorption of the two monoamines as a result of metformin’s effects on OCT1, OCT3 and SERT may contribute to the gastrointestinal side effects associated with metformin use. The research presented here has important implications for CNS drug delivery, as our results have expanded the chemical space, particularly the known substrates, of several transporters expressed in the BBB. v TABLE OF CONTENTS Acknowledgements ...................................................................................................................... iii Abstract ......................................................................................................................................... iv Table of Contents ......................................................................................................................... vi List of Tables ............................................................................................................................... xii List of Figures ............................................................................................................................. xiii Chapter 1. Membrane Transporters in Drug Absorption, Disposition and Targeting ...........1 Introduction to Membrane Transporters ......................................................................................1 SLC Transporters Play Important Roles in the Human Body ......................................................2 Transporters in Drug Development ..............................................................................................3 The Blood-Brain Barrier ..............................................................................................................4 Efflux Transporters and Drug-Drug Interactions at the Blood-Brain Barrier ..............................6 Influx Transporters at the Blood-Brain Barrier ............................................................................8 Uptake of Drugs into the Brain ....................................................................................................9 In vitro and in vivo Models of Blood-Brain Barrier Transport ..................................................10 Focus of Dissertation and Key Questions ..................................................................................11 Summary of Dissertation Chapters ............................................................................................16 Chapter 2 ................................................................................................................................16 Chapter 3 ................................................................................................................................17 Chapter 4 ................................................................................................................................18 Chapter 5 ................................................................................................................................18 vi Chapter 6 ................................................................................................................................19 References ..................................................................................................................................21 Chapter 2. Solute Carrier Transporters as Therapeutic Targets ...........................................27 Introduction ................................................................................................................................27 SLC12 Transporters as Targets of Diuretic Drugs .....................................................................34 SLC6 Transporters as Targets of Neuropsychiatric Drugs ........................................................36 Glucose Transporter Inhibitors ...................................................................................................38 Uric Acid Transporter Inhibitors ................................................................................................39 Glycine Transporter Inhibitors ...................................................................................................41 Bile Acid Transporter Inhibitors ................................................................................................42 Nutrient Transporter Inhibitors ..................................................................................................44 SLC-targeting Imaging Agents ..................................................................................................45 Strategies for Targeting SLC Transporters ................................................................................46 Inhibition of Transporter Function .........................................................................................46 Enhancement of Transporter Function ...................................................................................49 Circumventing Transporters ...................................................................................................51 Gene Therapy .........................................................................................................................51 Future Directions ........................................................................................................................52 References ..................................................................................................................................54 Chapter 3. Identification of Novel Ligands of the L-Type Amino Acid Transporter 1 (LAT1) ...........................................................................................................................................91 Introduction ................................................................................................................................91 vii Materials and Methods ...............................................................................................................93 Chemicals ...............................................................................................................................93 Cell Culture ............................................................................................................................93 Inhibition Screen and IC50 Determinations ............................................................................94 Trans-stimulation Studies .......................................................................................................94
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