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(BBB) Model for Drug Permeability Studies, and Application to Natural Product Establishment and validation of an immortalized in vitro human blood-brain barrier (BBB) model for drug permeability studies, and application to natural product derived leads Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Daniela Elisabeth Eigenmann aus Waldkirch, St. Gallen Basel, 2016 Original document stored on the publication server of the University of Basel edoc.unibas.ch This work is licenced under the agreement „Attribution Non-Commercial No Derivatives – 3.0 Switzerland“ (CC BY-NC-ND 3.0 CH) The complete text may be reviewed here: creativecommons.org/licenses/by-nc-nd/3.0/ch/deed.en Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Matthias Hamburger Prof. Dr. Laurent A. Decosterd Basel, den 08.12.2015 Prof. Dr. Jörg Schibler Dekan Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 3.0 Schweiz (CC BY-NC-ND 3.0 CH) Sie dürfen: Teilen — den Inhalt kopieren, verbreiten und zugänglich machen Unter den folgenden Bedingungen: Namensnennung — Sie müssen den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen. Keine kommerzielle Nutzung — Sie dürfen diesen Inhalt nicht für kommerzielle Zwecke nutzen. Keine Bearbeitung erlaubt — Sie dürfen diesen Inhalt nicht bearbeiten, abwandeln oder in anderer Weise verändern. Wobei gilt: Verzichtserklärung — Jede der vorgenannten Bedingungen kann aufgehoben werden, sofern Sie die ausdrückliche Einwilligung des Rechteinhabers dazu erhalten. Public Domain (gemeinfreie oder nicht-schützbare Inhalte) — Soweit das Werk, der Inhalt oder irgendein Teil davon zur Public Domain der jeweiligen Rechtsordnung gehört, wird dieser Status von der Lizenz in keiner Weise berührt. Sonstige Rechte — Die Lizenz hat keinerlei Einfluss auf die folgenden Rechte: o Die Rechte, die jedermann wegen der Schranken des Urheberrechts oder aufgrund gesetzlicher Erlaubnisse zustehen (in einigen Ländern als grundsätzliche Doktrin des fair use bekannt); o Die Persönlichkeitsrechte des Urhebers; o Rechte anderer Personen, entweder am Lizenzgegenstand selber oder bezüglich seiner Verwendung, zum Beispiel für Werbung oder Privatsphärenschutz. Hinweis — Bei jeder Nutzung oder Verbreitung müssen Sie anderen alle Lizenzbedingungen mitteilen, die für diesen Inhalt gelten. Am einfachsten ist es, an entsprechender Stelle einen Link auf diese Seite einzubinden. Quelle: http://creativecommons.org/licenses/by-nc-nd/3.0/ch/ Datum: 12.11.2013 To my dear friends and family Simplicity is the ultimate sophistication. Leonardo da Vinci (1452–1519) Table of contents List of abbreviations ........................................................................................................................... 11 Summary ............................................................................................................................................. 13 Zusammenfassung .............................................................................................................................. 16 1 Aim of the work .......................................................................................................................... 19 2 Introduction ................................................................................................................................ 23 2.1 Blood-brain barrier (BBB) ................................................................................................... 24 2.1.1 Historic background ............................................................................................................ 24 2.1.2 Structure and function of the BBB ...................................................................................... 24 2.1.3 Other barriers in the central nervous system (CNS) ............................................................ 29 2.1.4 Importance of the BBB for drug delivery to the brain ......................................................... 30 2.2 CNS drug discovery ............................................................................................................... 34 2.2.1 The burden of CNS disorders .............................................................................................. 34 2.2.2 Challenges in CNS drug discovery ...................................................................................... 34 2.2.3 How can the success rate of CNS drugs be improved? ....................................................... 36 2.2.4 CNS drug discovery and natural products ........................................................................... 36 2.2.5 GABAA receptors – example of an important pharmacological target in the CNS ............. 38 2.3 Models to predict brain penetration .................................................................................... 41 2.3.1 Brain penetration of drugs ................................................................................................... 41 2.3.2 Rule-based approaches and in silico models ....................................................................... 41 2.3.3 In vitro models ..................................................................................................................... 42 2.3.4 In vivo models ...................................................................................................................... 47 2.3.5 Favorable brain penetration characteristics of CNS drug candidates .................................. 48 2.3.6 Strategies for assessing brain penetration of lead candidates .............................................. 49 2.4 Bioanalysis .............................................................................................................................. 53 2.4.1 Definition ............................................................................................................................. 53 2.4.2 Bioanalytical techniques ...................................................................................................... 53 2.4.3 Liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS/MS) .... 54 2.4.4 Sample preparation for LC-MS/MS .................................................................................... 55 9 2.4.5 Quantitative bioanalysis by LC-MS/MS ............................................................................. 57 2.4.6 Method development ........................................................................................................... 58 2.4.7 Method validation ................................................................................................................ 60 2.4.8 Method application (analysis of study samples) .................................................................. 63 3 Results and discussion ............................................................................................................... 67 3.1 Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies ......................................................... 69 3.2 Validation of an immortalized human (hBMEC) in vitro blood-brain barrier model ............. 87 3.3 In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs ................................................................................................................................... 111 3.4 Development and validation of a LC-MS/MS method for assessment of an anti-inflammatory indolinone derivative by in vitro blood-brain barrier models ................................................ 139 4 Conclusions and outlook .......................................................................................................... 155 Acknowledgments ............................................................................................................................. 163 10 List of abbreviations ABC ATP-binding cassette AJ Adherens junction APCI Atmospheric pressure chemical ionization AUC Area under the curve BB19 Immortalized human brain capillary endothelial cells BBB Blood-brain barrier BCRP Breast cancer resistance protein BCSFB Blood-cerebrospinal fluid barrier BSCB Blood-spinal cord barrier Cal Calibrator CCL Cell layer capacitance CNS Central nervous system CSF Cerebrospinal fluid CV Coefficient of variation EMA European Medicines Agency ER Efflux ratio ESI Electrospray ionization EVOM Epithelial voltohmmeter FBS Fetal bovine serum FDA Food and Drug Administration F/T Freeze and thaw GABAA receptor γ-Aminobutyric acid type A receptor hBMEC Immortalized human brain microvascular endothelial cell line HBPCT Immortalized human brain pericyte cell line HC Hydrocortisone hCMEC/D3 Immortalized human cerebral microvascular endothelial cell line D3 HPLC High performance liquid chromatography I.S. Internal standard ISF Interstitial fluid JAM Junction-associated molecules LC-MS Liquid chromatography coupled to mass spectrometry LC-MS/MS Liquid chromatography coupled to triple (tandem) quadrupole mass spectrometry LC-UV/Vis Liquid chromatography coupled to ultraviolet/visible absorbance detection LLE Liquid-liquid extraction LLOQ Lower limit of quantification 11 LY Lucifer yellow MRM Multiple reaction monitoring MRP Multidrug resistance-associated protein MS Mass spectrometry MW Molecular weight Na-F
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