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Metabolism of Doping Agents Using in Vitro and in Vivo Models

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Metabolism of Doping Agents Using in Vitro and in Vivo Models Metabolism of doping agents using in vitro and in vivo models Lore Geldof Thesis submitted in fulfilment of the requirements for the degree of Doctor (PhD) in Biomedical Sciences Promotor Prof. Dr. ir. Peter Van Eenoo Co-promotor Dr. Leen Lootens 2016 Metabolism of doping agents using in vitro and in vivo models Lore Geldof1 Public defence on 1 July 2016 Promotor Prof. Dr. ir. Peter Van Eenoo1 Co-promotor Dr. Leen Lootens1 Examination Committee Chairman: Prof. Dr. Johan Van de Voorde2 Reading Committee: Dr. Pieter Van Renterghem1 Prof. Dr. Alain Verstraete3 Prof. Dr. Veronique Stove4 Prof. Dr. Christophe Stove5 Dr. Wim Van Thuyne6 Prof. Dr. Martial Saugy7 1 Doping Control Laboratory (DoCoLab), Department of Clinical Chemistry, Microbiology and Immunology (GE06), Ghent University, Ghent, Belgium 2 Department of Pharmacology (GE09), Ghent University, Ghent, Belgium 3 Laboratory of Toxicology, Department of Clinical Chemistry, Microbiology and Immunology (GE06), Ghent University, Ghent, Belgium 4 Laboratory of Clinical Biology – Metabolic diseases, Department of Clinical Chemistry, Microbiology and Immunology (GE06), Ghent University, Ghent, Belgium 5 Laboratory of Toxicology, Department of Bio-analysis (FW03), Ghent University, Ghent, Belgium 6 Eastman Chemical Company, Ghent ,Belgium 7 Swiss Laboratory for Doping Analyses, University of Lausanne, Switzerland “De korste weg is een illusie, de langste weg hobbelig traag. Volg je Hart en vindt het pad waar je onderweg lerend geniet…” Patrick Mundus Dankwoord Het ganse traject van mijn doctoraat is een heel boeiende reis geweest die zowel mijn groei als wetenschapper als mijn persoonlijke groei gestimuleerd heeft. Ik ben dan ook ontzettend dankbaar voor deze leerrijke ervaring. Het is niet altijd een even gemakkelijke weg geweest, af en toe werden er enkele omwegen toegevoegd. Gelukkig werd ik steeds omringd door mensen die mij opnieuw de juiste richting konden aangeven. Zonder al hun steun onderweg had ik de eindbestemming zeker niet bereikt! Ik wil hier dan ook iedereen stuk voor stuk oprecht bedanken voor hun, misschien soms onbewuste, bijdrage die ze hebben geleverd aan deze thesis. Als eerste zou ik graag mijn promotor Prof. Peter Van Eenoo willen bedanken om mij de kans te geven om mijn doctoraat te starten na mijn masterproef in DoCoLab. Bovendien stond hij mij telkens opnieuw met raad en daad bij en vormde hij een onuitputbare bron van inspiratie voor zowel nieuwe expermenten als te onderzoeken componenten. Ik ben hem eveneens dankbaar om mij op wetenschappelijk vlak verder te laten ontwikkelen door deelnames aan congressen en de bijhorende presentaties. Ik wel hem ook bedanken om mij de verantwoordelijkheid te geven om studenten te begeleiden tijdens hun masterproef. Het mogen meehelpen met het routine werk, zorgden voor een leuke variatie met het onderzoek. Ik wil eveneens mijn co-promotor Leen bedanken om mij op weg te zetten met de in vitro en in vivo modellen. En mij met haar kennis en ervaring bij te staan voor het uitvoeren van de muizenproeven. Deze gelegenheid wil ik zeker en vast ook aangrijpen om Koen te bedanken om mij zo veel kennis bij te brengen over LC-MS. Ik ben hem eveneens heel dankbaar om mij door zijn aanstekelijk wetenschappelijk enthousiasme telkens te blijven motiveren en me terug op weg te helpen als ik even het noorden kwijt was. Kris en Wim ben ik dankbaar om mij in te leiden in de wondere wereld van LC-MS en GC-MS respectievelijk en om mijn kennis omtrent de toestellen bij te schaven waar nodig. Ze hebben me telkens ook ontzettend goed bijgestaan bij mijn analyses en ze verleenden mij eveneens een uitstekende pechverhelping met de toestellen. Leen en Pieter wil ik eveneens als mede-eilandbewoners en Nik, Michaël, Simone, Peter J. van het andere eiland bedanken om het bureauwerk aangenamer te maken. Nik wil ik zeker ook nog eens extra bedanken voor al zijn hulp tijdens mijn masterproef en de zo opgebouwde kennis, die een goede basis vormden voor mijn verder onderzoek in DoCoLab. Ik zou Eva ook in het bijzonder een welgemeende dankjewel willen zeggen om haar levensvreugde en –visies met mij te delen. Je hebt me ongelofelijk geïnspireerd, zowel op wetenschappelijk als persoonlijk vlak. Ik wil je dan ook het allerbeste en een mooie toekomst wensen (hier in België of waar dan ook...)!!! Alle andere collega’s van DoCoLab Jan, Dominique, Fiona, Ann, Trui, Monica, Pascaline, Ruth en Steven wil ik bedanken voor alle teamwork en hulp met het labo en administratieve werk. Ik wil hen eveens bedanken voor de leuke sfeer in DoCoLab met de vele fantasierijke pauzes en de bijhorende pronostieken (voorjaarsklassiekers, ronde van Frankrijk en de mol). Het was leuk dat ik in het laatste jaar toch ook eens met de overwinning mocht gaan lopen. Mede dankzij jullie was dit ganse traject een boeiende maar vooral ook leuke ervaring. De studenten Jasper, Wouter en Ann-Sofie die ik heb mogen begeleiden tijdens hun masterproef wil ik bedanken voor hun inzet. Ik vond dit alvast heel leerrijk en leuk om jullie te mogen bijstaan. Dankjewel Lieselot Decroix voor de samenwerking in verband met de prostanozol studie. Ik wil hier eveneens alle andere studenten die in DoCoLab ontmoet heb gedurende hun stage/thesis bedanken. Ik wil hen dan ook het beste wensen bij hun verdere carriére en hoop dat hun ervaring in DoCoLab hierbij nog van pas komt. I want to thank all the people that I met during my stay at DoCoLab: Lance, Vinicius, Vinod, Juliana and many more. My thanks go also to all participants of the Cologne workshop for their useful contributions in the field of doping and the interesting discussions. This workshop keeps researchers open-minded and encourages researchers, including myself, to perform further research in this field. I am all the co-authors grateful for their cooperation and support. Thank you Prof. Francesco Botrè and Dr. Amy B. Cadwallader for your support to set up the in vitro protocol and Prof. Daniel Eichner, Thane Campbell and Vinod Nair for your cooperation with regard to the methylstenbolone and estradienedione study. Special thanks to Dr. Óscar Pozo for the help with the interpretation of LC-MS/MS product ion scan spectra, the identification of the fragmentation patterns and the corresponding figures. Ik wil hierbij ook Prof. Geert-Leroux Roels en Prof. Philip Meuleman bedanken om ons de mogelijk te bieden om met het chimeer muismodel te werken. Lieven Verhoye wil ik eveneens bedanken voor de assistentie met de muizenproeven en de verzorgsters van het animalarium voor het verzorgen van de muizen en onderhoud van de kooien. Prof. José Martins en Tim Courtin wil ik eveneens bedanken voor het uitvoeren van de NMR analyses. The members of the reading committee, Prof. Johan Van de Voorde, Dr. Pieter Van Renterghem, Prof. Alain Verstraete, Prof. Veronique Stove, Prof. Christophe Stove, Dr. Wim Van Thuyne and Prof. Martial Saugy, are acknowledged for their time to review this thesis and their valuable comments to improve this work. Ik wil bovendien ook mijn (plus)ouders bedanken voor de mogelijkheid die ze me gaven om verder te studeren en zo mijn kennis te laten verruimen. Ik wil hen bedanken voor hun onvoorwaardelijke steun tijdens mijn doctoraat. Mijn mama wil ik eveneens bedanken voor de vele kommetjes soep en kopjes thee met een zoetigheidje tijdens het studeren en bij het schrijven van mijn doctoraat. Ik wil mijn zus Inne ook bedanken voor de vele momenten van steun, leuke praatjes en belevenissen. Ik ben jou eveneens enorm dankbaar voor het ontwerpen van de kaft van mijn doctoraat, het ziet er echt prachtig uit! De rest van mijn familie (oma’s, opa’s, plusbroers, tantes, nonkels, neven en nichten,...) wil ik uiteraard ook bedanken voor de interesse in mijn onderzoek, om in mij te blijven geloven en om er steeds voor mij te zijn. Een bijkomende dankjewel aan de sterretjes in de hemel, Freddy en opa Julien. Bedankt Freddy om mij de Hakuna Matata filosofie bij te brengen! Bedankt opa om zo een warme, moedige, liefdevolle opa te zijn! Weet dat ik jullie bewonder en nog steeds naar jullie opkijk! Ik ben ook mijn vrienden en vriendinnen ontzettend dankbaar voor hun luisterend oor en interesse in mijn onderzoek, weet dat dit telkens veel voor mij betekend heeft. Een dikke merci aan Venera om mij te steunen en het vertouwen te geven om jouw getuige te mogen zijn, de paardrijdvrienden die zorgden voor de nodige ontspanning op en naast de paarden, de Izegemse vrienden voor de vele leuke avonden in en buiten het martkaffee, Evelyn voor de toffe etentjes en babbeltjes tussendoor en Marlies, Stephanie en Iréne om mij al vanaf de start aan de UGent te steunen en voor de vele plezante citytrips/etentjes/babbeltjes samen,... Ik wil eveneens de vele personen en vrienden vanop de trein bedanken om het pendelen op te vrolijken met een babbel en een lach. Ik wil de ongetwijfeld vele anderen die ik hierboven nog niet heb vermeld eveneens bedanken voor hun steun! Tenslotte wil ik uiteraard Kris bedanken om zo een geduldig, hulpvaardig en steunend kompas voor mij te zijn. Bedankt om mij zo de juiste richting aan te geven voor het afwerken van deze thesis! Een bijkomende dankjewel voor de vele kleine, muzikale, fietsende, wandelende, reizende afslagen die mijn energiepeil/stressniveau in balans hielden... Hartelijk Dank! Warm Thanks! Lore Table of Contents Table of Contents Table of Contents ................................................................................ I List of Tables .....................................................................................
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