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Mechanistic Study of Physicochemical and Biochemical Processes Mechanistic study of physicochemical and biochemical processes affecting intestinal absorption of the sesquiterpene lactone nobilin from multi-component systems in the Caco-2 model. Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von URSULA STEPHANIE THORMANN aus Bern (BE) Basel, 2015 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 3.0 Schweiz“ (CC BY-NC-ND 3.0 CH) lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licenses/by-nc-nd/3.0/ch/eingesehen werden. Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. G. Imanidis und Prof. Dr. H. E. U. Meyer zu Schwabedissen Basel, den 18. Februar 2014 Prof. Dr. J. Schibler 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 Meiner Familie Acknowledgements This Ph.D. thesis was carried out at the Institute of Pharma Technology of the School of Life Sciences- FHNW and was sponsored by the Alpinia Laudanum Institute of Phytopharmaceutical Sciences AG. I gratefully thank Prof. Dr. Georgios Imanidis for the excellent supervision of my Ph.D. work, especially, for his patience, for the long and fruitful discussions, for the profound explanations, for the long data fitting sessions, for the technical help with HPLC problems, and for encouraging me to explore new ways of reflecting a problem. Furthermore, I would like to thank Alpinia Laudanum Institute of Phytopharmaceutical Sciences AG for its financial support of my work. I am particularly grateful to Dr. Matthias Kreuter for the lively discussions and his ideas and Peter Altmann for the isolation of Nobilin and other helpful contributions. I would like to express my gratitude to Prof. Dr. Henriette E. Meyer zu Schwabedissen of the University of Basel (Division of Biopharmacy, Department of Pharmaceutical Sciences) for being the co-referee for this thesis. A special thank deserves Dr. Maria de Mieri of the University of Basel (Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences) for her excellent work of structure elucidation of the five degradation products of Nobilin and of suggesting a degradation mechanism. I am grateful to Dr. Markus Neuhauser of the University of Basel (Division of Inorganic Chemistry, Department of Chemistry) for the X-ray structure of the degradation product 1 and Dr. Claude Schärer of the HLS-FHNW (Institute of Chemistry und Bioanalytics) for his help with the isolation of the degradation products. I thank the bachelor student Sheela Verjee from the HLS-FHNW and the master student Rahel Hänggi of the University of Basel for their great work in the laboratory and their contributions to my thesis. Many thanks go to the people of the Institute of Pharma Technology. First of all I would like to thank Fabienne Thoenen who made me familiar with the cell culture and always provided great technical help in the laboratory. Additionally, I thank her, Dr. Michael Lanz, Martin Cavegn, and Dr. Cordula Stillhart for the amusing and reflecting discussions during break times and for their friendship and support. I also thank all other members of the Institute for having a great time with them. Last but not least I sincerely thank my family, especially, my parents Regula and Georg Thormann and my sister Kathrin Thormann and Adrian Megert for their love and support in what I am doing. Abstract The overall aim of this work was to investigate the intestinal absorption of the sesquiterpene lactone nobilin from the flowers of Anthemis nobilis L. (Chamomillae romanae flos) in the in vitro Caco-2 model and identify strategies for its improvement. The influence of physicochemical processes i.e., stability and solubility and biochemical processes i.e., bioconversion and membrane permeation by passive diffusion and carrier mediated transport on nobilin absorption were elucidated to gain a basic mechanistic understanding of the absorption of the compound. Physiologically based multi-compartment kinetic modeling was employed to delineate the influence of simultaneously acting phenomena. Based on this understanding, possibilities were finally explored to improve absorption of nobilin utilizing plant extract, formulation, and post-prandial application approaches. The thesis is divided into one theoretical part and three experimental studies, each addressing other aspects of physicochemical and biochemical processes affecting nobilin absorption. The first study focused on chemical degradation of nobilin and its solubility under conditions of concurrent degradation and the effect of biorelevant media used in the in vitro measurement of intestinal absorption. Purely aqueous medium (aq-TMCaco), fasted and fed state simulated intestinal fluid (FaSSIF-TMCaco and FeSSIF-TMCaco), and two liposomal formulations (LiposomesFaSSIF and LiposomesFeSSIF) with the same lipid concentration as FaSSIF-TMCaco and FeSSIF-TMCaco were used. Degradation products were identified by NMR and X-ray crystallography and the order of reaction kinetics was determined. Solubility was deduced with a mathematical model encompassing dissolution and degradation kinetics that took into account particle size distribution of the solid material. Degradation mechanism of nobilin involved water catalyzed opening of the lactone ring and transannular cyclization resulting in five degradation products. Degradation followed first order kinetics in aq-TMCaco and FaSSIF-TMCaco and higher order kinetics in FeSSIF-TMCaco and the two liposomal formulations while degradation in the latter media was reduced. Solubility of purified nobilin increased in the order: aq-TMCaco < FaSSIF-TMCaco < LiposomesFaSSIF < FeSSIF-TMCaco < LiposomesFeSSIF. Improvement of stability and solubility of nobilin was consistent with incorporation of the molecule into colloidal lipid particles. The developed kinetic model is proposed to be a useful tool for deducing solubility of a highly unstable compound with a wide particle size distribution. i Abstract ii In the second study, the role of bioconversion and carrier mediated efflux of conjugation products in the absorption mechanism of nobilin in the Caco-2 model and the impact of the extract of Chamomillae romanae flos and its ingredients on bioconversion and efflux was investigated. Permeation and bioconversion parameter values were deduced by means of kinetic multi-compartment modeling. Nobilin exhibited high permeability, low absorption and fast bioconversion producing glucuronide, cysteine conjugate, and glutathione conjugate that were transported by P-gp (the first two), apical MRP2 and basal MRP3 and possibly MRP1 out of the cell. Inhibition of efflux resulted in diminished bioconversion and improved absorption. The extract increased the relative fraction absorbed primarily by directly inhibiting bioconversion but also by reducing efflux. This effect of the extract was only partly explained by its individual ingredients. The transport-bioconversion interplay is shown to be a possible mechanism for increasing absorption of a compound undergoing extensive bioconversion. Plant extracts may increase absorption by this mechanism in addition to metabolic enzyme inhibition. The focus of the third study was the effect of biorelevant media and two lipid based formulations (SMEDSS1 and SMEDDS2) on in vitro absorption of nobilin applied as a pure compound or as a full ethanolic extract of Chamomillae romanae flos. Permeation and bioconversion parameters were deduced by means of kinetic multi-compartment modeling. FaSSIF-TMCaco reduced apical efflux of all conjugates but did not affect nobilin absorption while FeSSIF-TMCaco increased absorption which was attributed to the increased chemical stability in the medium and decreased bioconversion while permeability
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