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Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control

1
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden
2
Kenneth L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
3
Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute (SVA), SE-75189 Uppsala, Sweden
4
Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA
5
Institute of Biochemistry, Center for Preventive Doping Research, German Sport University, 50933 Cologne, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Markus R. Meyer
Metabolites 2021, 11(2), 85; https://doi.org/10.3390/metabo11020085
Received: 17 December 2020 / Revised: 22 January 2021 / Accepted: 27 January 2021 / Published: 1 February 2021
(This article belongs to the Section Pharmacology and Drug Metabolism)
Selective Androgen Receptor Modulators (SARMs) have anabolic properties but less adverse effects than anabolic androgenic steroids. They are prohibited in both equine and human sports and there have been several cases of SARMs findings reported over the last few years. The aim of this study was to investigate the metabolite profile of the SARM ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) in order to find analytical targets for doping control. Oral administration of ACP-105 was performed in horses, where blood and urine samples were collected over a time period of 96 h. The in vivo samples were compared with five in vitro incubation models encompassing Cunninghamella elegans, microsomes and S9 fractions of both human and equine origin. The analyses were performed using ultra-high performance liquid chromatography coupled to high resolution Q ExactiveTM OrbitrapTM mass spectrometry (UHPLC-HRMS). A total of 21 metabolites were tentatively identified from the in vivo experiments, of which several novel glucuronides were detected in plasma and urine. In hydrolyzed urine, hydroxylated metabolites dominated. The in vitro models yielded several biotransformation products, including a number of monohydroxylated metabolites matching the in vivo results. The suggested analytical target for equine doping control in plasma is a dihydroxylated metabolite with a net loss of two hydrogens. In urine, the suggested targets are two monohydroxylated metabolites after hydrolysis with β-glucuronidase, selected both due to prolongation of the detection time and the availability of reference material from the in vitro models. View Full-Text
Keywords: SARM; Selective Androgen Receptor Modulator; ACP-105; mass spectrometry; doping; horse; metabolites; microsomes; Cunninghamella elegans SARM; Selective Androgen Receptor Modulator; ACP-105; mass spectrometry; doping; horse; metabolites; microsomes; Cunninghamella elegans
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MDPI and ACS Style

Broberg, M.N.; Knych, H.; Bondesson, U.; Pettersson, C.; Stanley, S.; Thevis, M.; Hedeland, M. Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control. Metabolites 2021, 11, 85. https://doi.org/10.3390/metabo11020085

AMA Style

Broberg MN, Knych H, Bondesson U, Pettersson C, Stanley S, Thevis M, Hedeland M. Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control. Metabolites. 2021; 11(2):85. https://doi.org/10.3390/metabo11020085

Chicago/Turabian Style

Broberg, Malin N., Heather Knych, Ulf Bondesson, Curt Pettersson, Scott Stanley, Mario Thevis, and Mikael Hedeland. 2021. "Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control" Metabolites 11, no. 2: 85. https://doi.org/10.3390/metabo11020085

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