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Skin,Mucosal and Blood-Brain Barrier Kinetics

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Skin,Mucosal and Blood-Brain Barrier Kinetics FACULTY OF PHARMACEUTICAL SCIENCES DRUG Quality & Registration (DRUQUAR) Lab SKIN, MUCOSAL AND BLOOD-BRAIN BARRIER KINETICS OF MODEL CYCLIC DEPSIPEPTIDES: THE MYCOTOXINS BEAUVERICIN AND ENNIATINS Thesis submitted to obtain the degree of Doctor in Pharmaceutical Sciences Lien TAEVERNIER Promoter Prof. Dr. Bart DE SPIEGELEER FACULTY OF PHARMACEUTICAL SCIENCES Drug Quality & Registration (DruQuaR) Lab SKIN, MUCOSAL AND BLOOD-BRAIN BARRIER KINETICS OF MODEL CYCLIC DEPSIPEPTIDES: THE MYCOTOXINS BEAUVERICIN AND ENNIATINS Lien TAEVERNIER Master of Science in Drug Development Promoter Prof. Dr. Bart DE SPIEGELEER 2016 Thesis submitted to obtain the degree of Doctor in Pharmaceutical Sciences COPYRIGHT COPYRIGHT The author and the promotor give the authorization to consult and to copy parts of this thesis for personal use only. Any other use is limited by the Laws of Copyright, especially the obligation to refer to the source whenever results from this thesis are cited. Ghent, 9th of September 2016 The promoter The author Prof. Dr. Bart De Spiegeleer Lien Taevernier 3 ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS I never could have achieved this work on my own, therefore I wish to thank some very important people and address a few words to them. I consider myself fortunate to know you and I was honoured to be able to work together with you and learn a great deal from all of you. First of all, a special thank you to my promoter Prof. Dr. Bart De Spiegeleer. I am grateful that you gave me the opportunity to pursue my Ph.D. at DruQuaR. Your door was always open for me, even if it did not consider work. I really appreciate your excellent guidance these last four years and I am proud to say that I have learned a lot from you and from your lifelong experience. Thank you for the trust you have put into me and for always challenging me to bring my work to the next level. Working at DruQuaR has definitely contributed to my personal development, it has conquered its special place and I will never forget it. I also wish to thank the members of the examination committee, Prof. Dr. Christophe Stove as chairman, Prof. Dr. Sarah De Saeger, Prof. Dr. Serge Van Calenbergh, Prof. Dr. Antoon Bronselaer and Prof. Dr. Jos Hoogmartens, for critically reviewing this work. The interesting and dynamic discussions certainly improved the quality of this thesis. I acknowledge Ghent University, the Faculty of Pharmaceutical Sciences and the DruQuaR lab for the use of their facilities and funding. I would also like to thank Doctoral Schools for the educational support. This research work could never have been established without the financial support and scientific interest of the Special Research Fund (BOF 01D23812) of Ghent University. Furthermore, I would like to express my gratitude to the people that I worked with during collaboration projects. I’m grateful to Prof. Dr. Stijn Vansteelandt (Department Applied Mathematics, Computer Science and Statistics, Ghent University) for your help with the statistical analyses and interpretation of the adsorption results, Prof. Dr. Catherine Delesalle, Prof. Dr. Christian Burvenich (Department of Comparative Physiology and Biometrics, Ghent University) and Dr. Kathelijne Peremans (Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Ghent University) for your scientific contributions and Dr. Nathalie Roche and Evelien Vervaet (Department of Plastic and Reconstructive Surgery, UZ Ghent) for your commitment and excellent follow-up on human skin logistics. Also thank you to Dr. Leen De Vreese (Centre for Logic and Philosophy of Science, Ghent University) for your interesting philosophic input in our work about the mycotoxin definition. Sven Detroyer and Antoon Daneels, thank you for all your efforts and help 5 ACKNOWLEDGEMENTS during your master thesis at DruQuaR. I am also grateful to Laurent Dehennin from Porc Meat Zele NV for the provision of the porcine buccal mucosa. Lastly, thank you Prof. Dr. Ralf Hoffmann and Dr. Daniela Volke (Centre for Biotechnology and Biomedicine, University of Leipzig) for providing the experimental framework for the MALDI-MS analyses. I’m grateful to all my former and present DruQuaR co-workers: Dr. Jente Boonen for teaching me all about the Franz diffusion cell technique and Dr. Matthias D’Hondt for sharing your knowledge about chromatography and introducing me into the world of quality assurance. Thank you Dr. Sofie Stalmans, Dr. Evelien Wynendaele, Lieselotte Veryser and Nathalie Bracke for the interesting scientific discussions, for your contributions to many manuscripts, for your help during experiments and most importantly, thank you for being there for me in times of need. Han Yao, thank you for the nice atmosphere at our desk; when you return to China I hope to visit you there one day. Kirsten Vandercruyssen, Mathieu Verbeken, Dr. Sultan Suleman, Bert Gevaert, Frederick Verbeke, Xiaolong Xu, Sileshi Belew Yohannes, Yorick Janssens and Anne Kosgei, thank you all for your help and amazing workship. I really enjoyed our scientific discussions, our laughs and joyful evening activities. With some of you I also had some memorable moments at scientific conferences that will always stick to me. Also our DruQuaR weekends were truly fantastic. I will miss all of you, but I hope this is not a final “goodbye”. Finally, I wish to thank all my family & friends for every now and then, puncturing my Ph.D. bubble and therefore providing the necessary distractions. The parties, dinners and trips were always so much fun! Thank you all for your kind words, support and interest, you are really the best! A very special thank you is in place for the four most important people in my life. Mama, papa & Anja, for the past 27 years you have been my biggest support. Thank you for everything you always do to help me achieve my goals. I love you. Last, but certainly not least, thank you Jasper ♡. Your patience is endless, your love and encouraging and comforting words really helped me get through this last year. I am so much looking forward to our future together. I love you. Lien 6 LIST OF ABBREVIATIONS AND SYMBOLS LIST OF ABBREVIATIONS AND SYMBOLS Exposure time 15-ADON 15-Acetyldeoxynivalenol 3-ADON 3-Acetyldeoxynivalenol A Adenylation A Area ABC ATP binding cassette ACAT Acyl-CoA:cholesterol acyltransferase ACP Acyl carrier protein ACN Acetonitrile AF Aflatoxin Ahp Amino-hydroxy-piperidone Ala Alanine Ama Amino-methyl-acid Am(o)ya Amino-methyl-(oct)ynoic-acid Amp Amino-methoxy-piperidone AOH Alternariol AT Acyltransferase AT Averaging time ATP Adenosine triphosphate BBB Blood-brain barrier BEA Beauvericin BEH Ethylene bridged hybrid BMD Benchmark dose BSA Bovine serum albumin BW Body weight 7 LIST OF ABBREVIATIONS AND SYMBOLS C Condensation CART Classification and regression tree CB Cytochalasin B CD Capillary depletion CDP Cyclic depsipeptide CHAID Chi-squared automatic interaction detector CIT Citrinin Cl Plasma clearance CMDh Coordination Group for Mutual Recognition and Decentralised Procedures – Human CNS Central nervous system CONTAM Contaminants in the Food Chain CPG Compliance Policy Guides Cpl,ss,buccal Steady-state plasma concentration after buccal application CSH Charged surface hybrid CSF Cerebrospinal fluid CT Condensation-like Cv Concentration in vehicle Cy Heterocyclistation Cys Cysteine Cyt c Cytochrome c D Derringer desirability DDE Daily dermal exposure DDEmax Maximum daily dermal exposure DH Dehydration DMA Dimethylacetamide Dmh(e/y)a Dimethyl-hydroxy-(e/y)noic-acid DMSO Dimethylsulfoxide 8 LIST OF ABBREVIATIONS AND SYMBOLS DNA Deoxyribonucleic acid DON Deoxynivalenol DS Dose solution E Epimerisation ED Exposure duration EF Exposure frequency EFSA European Food Safety Authority EMA European Medicines Agency EMAN European Mycotoxins Awareness Network ENN Enniatin ESI Electrospray ionisation EtOH Ethanol EU European Union EV Event frequency F Formylation FA Fatty acid FA Formic acid FAO Food and Agriculture Organization of the United Nations FB1 Fumonisin B1 FDA Food and Drug Administration FDC Franz diffusion cell FID Flame ionisation detector FUS Fusaproliferin FUS-X Fusarenon-X GC Gas chromatography GLI Gliotoxin Gly Glycine H Heterocyclisation 9 LIST OF ABBREVIATIONS AND SYMBOLS HCA Hierarchical cluster analysis HDAC Histone deacetylase HIV Human immunodeficiency virus HPBCD Hydroxypropyl-β-cyclodextrin Hppa 3-Hydroxy-3-phenylpropanoic acid Ibu Amino-dimethyl-oxo-acid IC50 Inhibitory concentration, 50% ICR-CD-1 Institute for Cancer Research, Caesarean derived-1 ICV Intracerebroventricular IFN-γ Interferon-gamma IPCS International Programme on Chemical Safety IPM Isopropyl myristate IS Internal standard Jmax Maximum flux Jss Steady-state flux K Net brain clearance K1 Unidirectional blood-to-brain clearance kout Efflux rate constant kp Permeability coefficient kp,v Permeability coefficient in vehicle kp,w Permeability coefficient in water KR Ketoreduction KS Ketosynthase LD50 Lethal dose, 50% LMP Lysosomal membrane permeabilisation LOAEL Lowest observed adverse effect level LoD Limit of detection LoQ Limit of quantification 10 LIST OF ABBREVIATIONS AND SYMBOLS LPS Lipopolysaccharide M Methylation MALDI Matrix-assisted laser desorption/ionisation MeOH Methanol Mh(e/y)a Methyl-hydroxy-(e/y)noic-acid MLR Multiple linear regression MOMP Mitochondrial outer membrane permeabilisation MON Moniliformin MRM Multiple reaction monitoring MS Mass spectrometry MT Mycotoxin MTR Multiple time regression MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MW Molecular weight NCRI
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