Universität zu Köln

Thevis, Mario, Gerace, Enrico ORCID: 0000-0002-4499-4276, Thomas, Andreas ORCID: 0000-0003-1199-0743, Beuck, Simon, Geyer, Hans, Schloerer, Nils ORCID: 0000-0002-0990-9582, Kearbey, Jeffrey D., Dalton, James T. and Schaenzer, Wilhelm (2010). Characterization of in vitro generated metabolites of the selective androgen receptor modulators S-22 and S-23 and in vivo comparison to post-administration canine urine specimens. Drug Test. Anal., 2 (11-12). S. 589 - 599. HOBOKEN: WILEY. ISSN 1942-7611

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Abstract

Selective androgen receptor modulators (SARMs) have great therapeutic potential in various diseases including cancer cachexia, sarcopenia, and osteoporosis, and the number of drug candidates has been growing over the last decade. The SARM drug candidates S-22 and S-23 belong to one of the most advanced groups of androgen receptor modulators and are based on an arylpropionamide-derived core structure. Due to their anabolic effects, SARMs have been prohibited in elite sports and have been a subject of sports drug testing programmes since January 2008. Consequently, the structure of analytically useful urinary metabolites should be elucidated to provide targets for sensitive and retrospective analysis. In the present study, the phase-I and -II metabolism of S-22 and S-23 was simulated using hepatic human enzymes, and resulting metabolites were characterized by means of state-of-the-art mass spectrometric approaches employing high resolution/high accuracy Orbitrap mass spectrometry. Subsequently, the newly defined target compounds including the glucuronic acid conjugates of S-22 and S-23, their corresponding monohydroxylated and bishydroxylated analogs, as well as their B-ring depleted counterparts were implemented into an existing routine doping control procedure, which was examined for its specificity for the added substances. In order to obtain proof-of-concept data for authentic urine specimens, canine urine samples collected up to 72 h after oral administration of S-22 to dogs were analyzed using the established approach outlining the capability of the presented assay to detect the glucuronide of S-22 as well as the B-ring-depleted metabolite (M3) in all samples following therapeutic (31.4 mu g/kg) dosing. Finally, M3 was chemically synthesized, characterized by nuclear magnetic resonance spectroscopy and high resolution/high accuracy mass spectrometry, and chosen as primary target for future doping control analyses. Copyright (C) 2010 John Wiley & Sons, Ltd.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Thevis, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerace, Enrico UNSPECIFIED orcid.org/0000-0002-4499-4276 UNSPECIFIED Thomas, Andreas UNSPECIFIED orcid.org/0000-0003-1199-0743 UNSPECIFIED Beuck, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Geyer, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Schloerer, Nils UNSPECIFIED orcid.org/0000-0002-0990-9582 UNSPECIFIED Kearbey, Jeffrey D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dalton, James T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaenzer, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-493167
DOI:	10.1002/dta.211
Journal or Publication Title:	Drug Test. Anal.
Volume:	2
Number:	11-12
Page Range:	S. 589 - 599
Date:	2010
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1942-7611
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TANDEM MASS-SPECTROMETRY; NONSTEROIDAL ANDROGEN; PHARMACOKINETICS; DISPOSITION; MOUSE; LIVER Multiple languages Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49316