Universität zu Köln

Lagojda, Andreas, Kuehne, Dirk, Krug, Oliver, Thomas, Andreas ORCID: 0000-0003-1199-0743, Wigger, Tina, Karst, Uwe, Schaenzer, Wilhelm and Thevis, Mario (2016). Identification of selected in vitro-generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes. Eur. J. Mass Spectrom., 22 (2). S. 49 - 60. W SUSSEX: IM PUBLICATIONS. ISSN 1751-6838

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Abstract

Research into developing anabolic agents for various therapeutic purposes has been pursued for decades. As the clinical utility of anabolic-androgenic steroids has been found to be limited because of their lack of tissue selectivity and associated off-target effects, alternative drug entities have been designed and are commonly referred to as selective androgen receptor modulators (SARMs). While most of these SARMs are of nonsteroidal structure, the drug candidate MK-0773 comprises a 4-aza-steroidal nucleus. Besides the intended therapeutic use, SARMs have been found to be illicitly distributed and misused as doping agents in sport, necessitating frequently updated doping control analytical assays. As steroidal compounds reportedly undergo considerable metabolic transformations, the phase-I metabolism of MK-0773 was simulated using human liver microsomal (HLM) preparations and electrochemical conversion. Subsequently, major metabolic products were identified and characterized employing liquid chromatography-high-resolution/high-accuracy tandem mass spectrometry with electrospray (ESI) and atmospheric pressure chemical ionization (APCI) as well as nuclear magnetic resonance (NMR) spectroscopy. MK-0773 produced numerous phase-I metabolites under the chosen in vitro incubation reactions, mostly resulting from mono-and bisoxygenation of the steroid. HLM yielded at least 10 monooxygenated species, while electrochemistry-based experiments resulted predominantly in three monohydroxylated metabolites. Elemental composition data and product ion mass spectra were generated for these analytes, ESI/APCI measurements corroborated the formation of at least two N-oxygenated metabolites, and NMR data obtained from electrochemistry-derived products supported structures suggested for three monohydroxylated compounds. Hereby, the hydroxylation of the A-ring located N-bound methyl group was found to be of particular intensity. In the absence of controlled elimination studies, the produced information enables the implementation of new target analytes into routine doping controls and expands the focus of anti-doping efforts concerning this new anabolic agent.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lagojda, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuehne, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Krug, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Andreas UNSPECIFIED orcid.org/0000-0003-1199-0743 UNSPECIFIED Wigger, Tina UNSPECIFIED UNSPECIFIED UNSPECIFIED Karst, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaenzer, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Thevis, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-289235
DOI:	10.1255/ejms.1415
Journal or Publication Title:	Eur. J. Mass Spectrom.
Volume:	22
Number:	2
Page Range:	S. 49 - 60
Date:	2016
Publisher:	IM PUBLICATIONS
Place of Publication:	W SUSSEX
ISSN:	1751-6838
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPECTROMETRY; SIMULATION; DISCOVERY; SAFETY; SARM Multiple languages Physics, Atomic, Molecular & Chemical; Spectroscopy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28923