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Drug Metabolites Formed by Cunninghamella Fungi Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 186 Drug Metabolites Formed by Cunninghamella Fungi Mass Spectrometric Characterization and Production for use in Doping Control AXEL RYDEVIK ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-8906-9 UPPSALA urn:nbn:se:uu:diva-220906 2014 Dissertation presented at Uppsala University to be publicly examined in B:41, BMC, Husargatan 3, Uppsala, Friday, 9 May 2014 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor David Cowan (King's College, Department of Forensic and Analytical Science). Abstract Rydevik, A. 2014. Drug Metabolites Formed by Cunninghamella Fungi. Mass Spectrometric Characterization and Production for use in Doping Control. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 186. 46 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-8906-9. This thesis describes the in vitro production of drug metabolites using fungi of the Cunninghamella species. The metabolites were characterized with mainly liquid chromatography-mass spectrometry using ion-trap and quadrupole-time-of-flight instruments. A fungal in vitro model has several advantages e.g., it is easily up-scaled and ethical problems associated with animal-based models are avoided. The metabolism of bupivacaine and the selective androgen receptor modulators (SARMs) S1, S4 and S24 by the fungi Cunninghamella elegans and Cunninghamella blakesleeana was investigated. The detected metabolites were compared with those formed in vitro and in vivo by human and horse and most phase I metabolites formed by mammals were also formed by the fungi. The higher levels of bupivacaine metabolites in the fungal samples allowed an extensive mass spectrometric structural characterization which shows that the fungi are relevant metabolic models. Glucuronides are important drug metabolites but they are difficult to synthesize. The discovery that the fungus Cunninghamella elegans formed large amounts of glucosides led to the idea that they could be used to form glucuronides. A new concept was developed where a fungal incubate containing a SARM S1 glucoside was mixed with the free radical tetramethylpiperidinyl-1-oxy (TEMPO), sodium bromide and sodium hypochlorite which produced a glucuronide. Isolation and characterization by nuclear magnetic resonance spectroscopy proved that the new method could produce glucuronides for use as reference material. An investigation of reactive metabolite formation of the drugs paracetamol, mefenamic acid and diclofenac by the fungus Cunninghamella elegans was performed. It was demonstrated for the first time that the fungus could produce glutathione, glutathione ethyl-ester, cysteine and N- acetylcysteine conjugates that are indicative of a preceding formation of reactive intermediates. A comparison with conjugates formed by human liver microsomes showed that both models formed identical metabolites. The presented investigations prove that Cunninghamella fungi are relevant drug metabolism models. They show that the fungi to a large extent forms the same metabolites as mammals and that they can produce metabolites for use as reference material in, e.g. doping control. It was also demonstrated that the fungal model can be used in the important assessment of drug toxicity. Keywords: Cunninghamella blakesleeana, Cunninghamella elegans, Doping Control, Drug Metabolites, Glucuronide Production, Mass Spectrometry, Reactive Metabolites, Reference Material, Structural Characterization Axel Rydevik, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden. © Axel Rydevik 2014 ISSN 1651-6192 ISBN 978-91-554-8906-9 urn:nbn:se:uu:diva-220906 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-220906) This thesis is dedicated to all those who have ever wanted a thesis dedicated to them. List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Rydevik, A., Bondesson, U., Hedeland, M. (2012) Structural elucidation of phase I and II metabolites of bupivacaine in horse urine and fungi of the Cunninghamella species using liquid chromatography/multi-stage mass spectrometry. Rapid Com- munications in Mass Spectrometry, 26(11):1338–1346. II Rydevik, A., Thevis, M., Krug, O., Bondesson, U., Hedeland, M. (2013) The fungus Cunninghamella elegans can produce human and equine metabolites of selective androgen receptor modulators (SARMs). Xenobiotica, 43(5):409-420. III Rydevik, A., Bondesson, U., Thevis, M., Hedeland, M. (2013) Mass spectrometric characterization of glucuronides formed by a new concept, combining Cunninghamella elegans with TEMPO. Journal of Pharmaceutical and Biomedical Analysis, 84:278-284. IV Rydevik, A., Lagojda, A., Thevis, M., Bondesson, U., Hede- land, M. (2014) Isolation and characterization of a β- glucuronide of hydroxylated SARM S1 produced using a com- bination of biotransformation and chemical oxidation. In manu- script. V Rydevik, A., Hansson, A., Hellqvist, A., Bondesson, U., Hede- land, M. (2014) A novel trapping system for the detection of re- active drug metabolites using the fungus Cunninghamella ele- gans and high resolution mass spectrometry. In manuscript. Reprints were made with kind permission from the publishers. Additional paper not included in this thesis Guddat, S., Fußhöller, G., Beuck, S., Thomas, A., Geyer, H., Rydevik, A., Bondesson, U., Hedeland, M., Lagojda, A., Schänzer, W., Thevis, M. (2013) Synthesis, characterization, and detection of new oxandrolone metabolites as long-term markers in sports drug testing. Analytical and Bioanalytical Chemistry, 405(25):8285-8294. Contents Introduction ..................................................................................................... 9 Drug metabolism ........................................................................................... 11 Cunninghamella fungi .................................................................................. 13 Identification of drug metabolites ................................................................. 15 Analytical strategy for the identification of metabolites .......................... 15 Aims .............................................................................................................. 18 Results ........................................................................................................... 19 Discussion ..................................................................................................... 23 The fungi as a metabolism model ............................................................. 23 Drug metabolite production using fungi of the species Cunninghamella ....................................................................................... 28 Conclusions ................................................................................................... 33 Future studies ................................................................................................ 34 Svensk sammanfattning / Swedish summary ................................................ 35 Acknowledgements ....................................................................................... 38 References ..................................................................................................... 40 Abbreviations C. blakesleeana Cunninghamella blakesleeana C. elegans Cunninghamella elegans CYP Cytochrome P450 DDA Data-Dependent Acquisition EMA European Medicines Agency FDA Food and Drug Administration HPLC High Performance Liquid Chromatography MS Mass Spectrometry MS/MS Tandem mass spectrometry MSn Multiple-stage mass spectrometry m/z Mass-to-charge ratio NMR Nuclear Magnetic Resonance Q-ToF Quadrupole-Time-of-Flight mass analyzer SARM Selective Androgen Receptor Modulator TEMPO Tetramethylpiperidinyl-1-oxy UPLC Ultra Performance Liquid Chromatography Introduction The Olympic Games in Athens in 2004 led to many more confirmed cases of doping than what was expected based on previous games [1]. In 2012 sam- ples from those Olympic Games were analyzed again using new methods, instruments and materials in an attempt to see if there were more doping cases that had not been discovered back in 2004. Thanks to the discovery that the fungus Cunninghamella elegans was able to produce two new long- term metabolites two medalists were caught for using the anabolic steroid oxandrolone and were subsequently stripped of their medals [2,3]. These cases would never have been discovered if it hadn’t been for metabolic stud- ies of drugs. Thus they make an excellent example of the importance of such studies. The drugs being developed today are generally intended for therapeutic purposes; however some of them will be used for illicit purposes such as doping or drug abuse which means that there is a need to analyze them in doping control and forensic analysis. For all of these different areas of use it is important to know how the drugs are metabolized and how they can be detected by analyzing either the parent substance or its metabolites. This requires models that can be used to investigate how a drug is metabolized and production methods that can be used to create the metabolites for use as reference material. In doping control and forensic analysis it is of interest to look at metabo- lites since a metabolite indicates that the substance has passed
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