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Development of Chromatographic Methods and Their Applications for the Analysis of Chiral Drug Metabolism by Enzymes Altered During Pregnancy

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Development of Chromatographic Methods and Their Applications for the Analysis of Chiral Drug Metabolism by Enzymes Altered During Pregnancy Research Collection Doctoral Thesis Development of chromatographic methods and their applications for the analysis of chiral drug metabolism by enzymes altered during pregnancy Author(s): Korner-Wyss, Sara Publication Date: 2015 Permanent Link: https://doi.org/10.3929/ethz-a-010361935 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 22444 DEVELOPMENT OF CHROMATOGRAPHIC METHODS AND THEIR APPLICATIONS FOR THE ANALYSIS OF CHIRAL DRUG METABOLISM BY ENZYMES ALTERED DURING PREGNANCY A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH Zurich (Dr. sc. ETH Zurich) presented by SARA KORNER-WYSS Msc ETH Pharm. Sc, ETH Zurich born on 25.02.1981 citizen of Bern accepted on the recommendation of Prof. Dr. Karl-Heinz Altmann, examiner Prof. Dr. Ursula Quitterer, co-examiner Dr. Irmgard A. Werner, co-examiner 2015 An expert is a person who has made all the mistakes that can be made in a very narrow field. Niels Bohr (1885-1962) Dank Ich bedanke mich herzlich bei allen, die mich in den letzten Jahren unterst¨utzthaben und zum Gelingen dieser Arbeit beigetragen haben. Ganz besonders bedanke ich mich bei Herrn Prof. Karl-Heinz Altmann f¨urdas Vertrauen und die M¨oglichkeit unter seiner Leitung zu promovieren. Frau Prof. Ur- sula Quitterer bin ich sehr dankbar, dass sie bereit war das Korreferat f¨urdiese Arbeit zu ¨ubernehmen. Frau Dr. Irmgard A. Werner danke ich herzlich, dass sie mir die M¨oglichkeit gegeben hat in ihrer Gruppe die Doktorarbeit zu machen und sie in mir die Faszination zur Gaschromatographie wecken konnte. Ich bedanke mich f¨ur die Unterst¨utzungund Ratschl¨age,wenn ich nicht weiter wusste und daf¨ur,dass ich meine Arbeit mit grosser Unabh¨angigkeit ausf¨uhrendurfte. Ein weiteres Dankesch¨ongeht an die ¨ubrigeAnalytikgruppe mit Danielle L¨uthi, Ruth Alder und Philipp Manser, f¨urihre grosse Unterst¨utzung und Hilfe in allen Belangen sowie die interessanten Diskussionen. Zudem danke ich auch meinen Mas- terstudenten Luca Castelnovo, Hulda Brem und Angela Tschabold, die mit grossem Einsatz mein Projekt weitergebracht haben. Auch der Firma Brechb¨uhler AG, davon insbesondere Urs Hofstetter, Benjamin Oberlin und Ren´eWaldner danke ich f¨urden stets prompten und hilfreichen tech- nischen Support. Wobei ich Urs herzlich f¨ur seine ausgezeichnete Unterst¨utzungbei GC Fragen und Problemen und die guten Tipps und Tricks danke. Der Firma BGB Analytik AG und davon im Speziellen Georg Hottinger und Bernhard Fischer danke ich f¨urszur Verf¨ugung stellen von zahlreichen chiralen S¨aulenund Material f¨urdie GC-Analysen. Der Gruppe Radiopharmazie unter Prof. Roger Schibli spreche ich ebenfalls ein herzliches Dankesch¨onaus, da ich bei Seminaren, Vortr¨agenund anderen Gruppen- aktivit¨atenstets willkommen war und mich als einen erweiterten Teil dieser Gruppe f¨uhlendurfte. Dr. Selena Sephton danke ich f¨urdie gute Zusammenarbeit und dass ich bei chemischen Fragen ein offenes Ohr bei ihr fand. Auch bei PD Dr. Stefanie Kr¨amerbedanke ich mich f¨urdie Unterst¨utzungbei Fragen zu biopharmazeutischen Themen. Ausserdem danke ich Monica Langfritz f¨urihren IT-Support. e Ganz herzlich danke ich auch der Mittagsrunde, die Dr. Cindy Fischer, Roger Slavik, Romana Meletta, Dr. Adrienne Herde, PD Dr. Stefanie Kr¨amer,Dr. Linjing Mu, Claudia Keller, Dr. Thomas Betzel und Silvan Boss einschliesst, f¨urdie vielen guten und motivierenden Gespr¨ache ¨uber wissenschaftliche, aber auch allt¨agliche Themen und nat¨urlich auch f¨urdie auflockernden Abenden und Unternehmungen. Ein zus¨atzlicher grosser Dank geht an meine Familie, meine Freunde, das gesamte T¨odi-Apotheke Team, und ganz speziell an meinen Malala Lukas Korner. F¨urihre Unterst¨utzung,Geduld und Aufmunterung zu jeder Zeit bin ich sehr dankbar. Abstract During pregnancy, the female body undergoes important changes not only anatomi- cally, but also physiologically. These changes can lead to alterations in drug response and drug metabolism or even the emergence of new biological targets. Due to the scarcity of pharmacokinetic and pharmacodynamic data on newer and particularly chiral drugs, mainly "old drugs" are used during gestation, even though these com- pounds are not often the first choice treatment. In light of this situation, in vitro methods for the assessment of chiral drug metabolism during pregnancy is of significant interest and importance. With newly developed gas chromatographic (GC) methods for chiral and also non-chiral ap- plications, separation of drug enantiomers and their metabolites were successfully performed. Two model compounds, with poor knowledge of safe use in pregnancy, were selected to establish in vitro methods, methylphenidate (MPH), a commonly used drug for the treatment of the attention deficit hyperactivity disorder (ADHD) in children and adults, and tramadol (TMD), a weak µ-receptor agonist for the treatment of moderate-severe pain. Both compounds are commercially available as racemic mixtures. For a few years, methylphenidate is also approved in enantiomeric form. Because samples with high water content or improper handling of chiral GC columns rapidly lead to column impairment and unreliable results, an option for chiral GC column state and performance check was needed. Since no test mixture for such conditions was available, a new chiral test mixture for cyclodextrin based (CD) stationary phases with versatile applicability was developed. The mixture consists of twelve enantiomer pairs with different functional groups and was tested on 14 chiral CD-columns. Successful analysis was obtained and no co-elution of any compound was observed. Generally best enantiomeric separation was achieved with β-CD capillary columns. Thereof, on one column all enantiomers were separated (BGB-176SE, BGB Analytics). On the column Beta DexTM 325 (Supelco), besides methylphenidate, every enantiomer pair was separated. On other columns (α-, β-, γ-CD) at least one enantiomer pair was baseline separated (Rs ≥ 1.5). The elution of the enantiomers still occurred in random order. Since different mechanisms are responsible for chiral recognition on cyclodextrins, separation efficiency and elution order are difficult to predict. However, the two enantiomeric forms of γ-valerolactone showed the same elution order on all columns. It is assumed to be the result of a i predominant inclusion-interaction with the cyclodextrin molecules. For automated, highly sensitive and robust detection and for quantitative anal- ysis of chiral drug molecules and their metabolites, new analytical protocols were established. Such a method consists of automated sample preparation coupled to GC-MSD procedures with large volume injections (LVI > 10 µL) and pre-column backflushing (BKF) for mild evaporation conditions. This allows the analysis of thermo-labile compounds like methylphenidate. Furthermore, the sample matrix with potential risk to contaminate the analytical column or disturbing the analysis, is removed with BKF and extends the column lifetime. Additionally, high boiling substances are analyzable with successful removal of solvent prior to reaching the analytical column and enhanced analyte sensitivity is obtained. This is of particular interest for chiral GC columns, susceptible to solvent-induced harm. Efforts to develop liquid chromatographic methods (HPLC) to complement the GC methods did not lead to advantages, because sensitivity and screening capability using the same method were reduced with HPLC. Automated sample preparation was performed using the miniaturized extraction method micro extraction by packed sorbent (MEPS), where total solvent volumes of about 1 mL and minimal analyte volumes of 10 µL allowed successful extractions from a broad range of different matrices like water or buffer (saliva, blood or plasma would also be possible). Sample preparation with MEPS was beneficial in analyte enrichment but also in exchange of solvent, since water has to be avoided for di- rect GC analyses. The resulting MEPS-LVI-BKF-GC-MSD methods for chiral and non-chiral applications exhibited high sensitivity for the model compounds methyl- phenidate and tramadol. Other compounds (amphetamine, ibuprofen, cocaine, pen- tobarbital, tolperisone) also were successfully analyzed with the same method and highly sensitive mass selective detection. With a set of enzymes, whose expression levels are known to be important dur- ing pregnancy (e.g. carboxylesterase, cytochrome P450 2D6, 3A4), the model com- pounds methylphenidate and tramadol were analyzed. Carboxylesterase 1 (CES1), a serine hydrolase, was in a first attempt investigated for stability and optimal activity conditions, which are already known for cytochrome P450 enzymes (CYP). In metabolic experiments with chiral MEPS-LVI-BKF-GC-MSD analysis, racemic methylphenidate (MPH) was mainly stereoselectively metabolized by CES1 to ri- talinic acid (RA), the predominant metabolite of MPH. Also esterification could be demonstrated by formation of the parent compound in presence of ritalinic acid, methanol and CES1. To our knowledge it is the first time to be demonstrated. Methylphenidate was just weakly metabolized by CYP2D6, but no metabolite for- mation was detected and no stereoselectivity could be determined. With CYP3A4 no metabolism was observed. Tramadol showed low CES1 mediated metabolism, but without the appearance of formed metabolites or stereopreference. In contrast, CYP2D6
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