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Steroids 78 (2013) 44–52

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Steroids 78 (2013) 44–52 Steroids 78 (2013) 44–52 Contents lists available at SciVerse ScienceDirect Steroids journal homepage: www.elsevier.com/locate/steroids Alternative long-term markers for the detection of methyltestosterone misuse ⇑ C. Gómez a,b, O.J. Pozo a, J. Marcos a,b, J. Segura a,b, R. Ventura a,b, a Bioanalysis Research Group, IMIM-Hospital del Mar, Barcelona, Spain b Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain article info abstract Article history: Methyltestosterone (MT) is one of the most frequently detected anabolic androgenic steroids in doping Received 21 May 2012 control analysis. MT misuse is commonly detected by the identification of its two main metabolites Received in revised form 28 September excreted as glucuronide conjugates, 17a-methyl-5a-androstan-3a,17b-diol and 17a-methyl-5b-andro- 2012 stan-3a,17b-diol. The detection of these metabolites is normally performed by gas chromatography–mass Accepted 10 October 2012 spectrometry, after previous hydrolysis with b-glucuronidase enzymes, extraction and derivatization Available online 2 November 2012 steps. The aim of the present work was to study the sulphate fraction of MT and to evaluate their potential to improve the detection of the misuse of the drug in sports. MT was administered to healthy volunteers Keywords: and urine samples were collected up to 30 days after administration. After an extraction with ethyl ace- Methyltestosterone Sulphate tate, urine extracts were analysed by liquid chromatography tandem mass spectrometry using electro- Metabolism spray ionisation in negative mode by monitoring the transition m/z 385 to m/z 97. Three diol sulphate LC–MS/MS metabolites (S1, S2 and S3) were detected. Potential structures for these metabolites were proposed after Doping analysis solvolysis and mass spectrometric experiments: S1, 17a-methyl-5b-androstan-3a,17b-diol 3a-sulphate; S2, 17b-methyl-5a-androstan-3a,17a-diol 3a-sulphate; and S3, 17b-methyl-5b-androstan-3a,17a-diol 3a-sulphate. Synthesis of reference compounds will be required in order to confirm the structures. The retrospectivity of these sulphate metabolites in the detection of MT misuse was compared with the obtained with previously described metabolites. Metabolite S2 was detected up to 21 days after MT administration, improving between 2 and 3 times the retrospectivity of the detection compared to the last long-term metabolite of MT previously described, 17a-hydroxy-17b-methylandrostan-4,6-dien-3-one. Ó 2012 Elsevier Inc. All rights reserved. 1. Introduction techniques like liquid chromatography-tandem mass spectrometry (LC–MS/MS) due to the limitation of ionizable groups [6]. Methyltestosterone (MT, 17b-hydroxy-17a-methylandrost-4- In the doping control field, the best marker for the detection of a en-3-one) is a synthetic anabolic androgenic steroid (AAS) used drug administration is not always the most abundant metabolite but in sports to increase muscular mass and to improve performance. the one which can be detected for the longest period (the so-called MT is one of the most frequently detected AAS in doping analysis long-term metabolites). Therefore, metabolic studies are helpful in [1]. Therefore, antidoping control laboratories need to develop order to detect alternative long-term metabolites. During the last strategies to improve the detection of its misuse. years, the use of LC–MS/MS has allowed the detection of several The use of MT is normally screened by the detection of the two long-term metabolites for some AAS like stanozolol, methandienone main metabolites, 17a-methyl-5a-androstan-3a,17b-diol (M1) or testosterone [7–9]. In the case of MT, other minor metabolites and 17a-methyl-5b-androstan-3a,17b-diol (M2) (Fig. 1) which detectable by LC–MS/MS like 17a-hydroxy-17b-methylandrost- were firstly described by Rongone and Segaloff [2]. The detection 4,6-dien-3-one (M3) or 17a-hydroxy-17b-methylandrost-4-en-3- of these metabolites is commonly performed by gas chromatogra- one (M4) [10] have been reported, (Fig. 1). In addition to that, other phy–mass spectrometry (GC–MS), with previous hydrolysis with metabolites like 17b-hydroxymethyl-17a-methyl-18-norandrosta- b-glucuronidase and derivatization steps [3–5]. Hydrolysis is com- 4,13-dien-3-one (M5) [11] or 17b-methyl-5a-androstan-3a,17a- pulsory since M1 and M2 are mainly excreted as conjugates with diol (M6) and 17b-methyl-5b-androstan-3a,17a-diol (M7) [12] have glucuronic acid while the derivatization and subsequent GC–MS been reported by using GC–MS/MS or GC–MS after b-glucuronidase analysis is required since M1 and M2 are poorly detectable by other hydrolysis (Fig. 1). While M5 is excreted as glucuronide, the occur- rence of M3, M4, M6 and M7 in urine can be explained by epimeriza- tion at the C17 after conjugation with a sulphate moiety. ⇑ Corresponding author. Address: Bioanalysis and Analytical Services Research Group, IMIM, Institut de Recerca Hospital del Mar, Doctor Aiguader, 88, 08003 17b-Sulphates are spontaneously hydrolysed in urine to several Barcelona, Spain. Tel.: +34 93 3160471; fax: +34 93 3160499. dehydratation products, and to the 17a-hydroxy-17b-methyl epi- E-mail address: [email protected] (R. Ventura). mers [12–14] (Fig. 1). Among all those metabolites, it was demon- 0039-128X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.steroids.2012.10.008 C. Gómez et al. / Steroids 78 (2013) 44–52 45 DETECTED IN URINE M1-Gluc M2-Gluc OH CH 3 S1 OH OH PHASE II CH CH 3 3 OH HO S-O S2 3 O-SO3H H CH CH 3 3 Gluc-O Gluc-O H H HO S-O S1 HO S-O 3 3 H H OH OH O-SO H OH PHASE I 3 CH CH CH CH 3 3 3 3 OH O-SO H CH 3 S3 3 CH M1 OH M2 3 OH HO3S-O HO3S-O H H H H O-SO H 3 CH OH OH 3 CH3 CH Gluc-O Gluc-O 3 H M6-Gluc H Gluc-O H Gluc-O O MT H M7-Gluc O-SO3H CH 3 OH OH CH 2 CH CH 3 3 OH CH O 3 M5 O O O-Gluc CH 2 O-SO H O M4 3 CH 3 CH 3 O O OH CH 3 M5-Gluc O M3 Fig. 1. Location of the reported metabolites S1, S2 and S3 in the metabolic pathways for methyltestosterone based on previously reported results [2,3,10–12]. strated that the LC–MS/MS detection of M3 provides the highest ret- stan-3b,17b-diol and 17a-methyl-5b-androstan-3b,17b-diol were rospectivity [10]. This fact shows the potential usefulness of metab- purchased from Research Plus, Inc. (Bayonne, NJ, USA). Boldenone olites conjugated with sulphates for the long-term detection of MT was obtained from Sigma (Steinheim, Germany). misuse. Sulphate metabolites are known to be important for some Tert-butyl methyl ether (TBME, HPLC grade), ethyl acetate (HPLC endogenous steroids and they have also been described for exoge- grade), acetonitrile and methanol (LC gradient grade), formic acid nous AAS [4,15–17]. However, a comprehensive study of this phase (LC/MS grade), potassium carbonate, sulphuric acid, sodium II biotransformation for MT has not been performed. hydroxide, di-sodium hydrogen phosphate, sodium hydrogen phos- The use of LC–MS/MS is gradually becoming more important for phate, sodium chloride, ammonia hydroxide, ammonium chloride, the detection of phase I and II metabolites of doping agents [7– ammonium iodide, and 2-mercaptoethanol (all analytical grade) 10,17–23]. Recent studies by our group showed the potential of were purchased from Merck (Darmstadt, Germany). Ammonium LC–MS/MS for the direct detection of sulphate metabolites of other formate (HPLC grade) and the alkane standard mixture (C20–C40) AAS. Minor metabolites of boldenone excreted as sulphate conju- were obtained from Sigma–Aldrich (Steinheim, Germany). gates (0.01% of the administered dose) did provide the same retro- N-Methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) was pur- spectivity than the main glucuronide metabolites [18]. chased from Macherey-Nagel (Düren. Germany). b-Glucuronidase The aim of this work was to study metabolites of MT conjugated from Escherichia coli K12 was obtained from Roche Diagnostics with sulphate using LC–MS/MS analysis, and to evaluate their po- (Mannheim, Germany). Detectabuse™ XAD-2 extraction columns tential to improve the detection of MT compared with previously were purchased from Biochemical Diagnostics, Inc. (Edgewood, described metabolites. NY, USA). Milli Q water was obtained by a Milli-Q purification sys- tem (Millipore Ibérica, Barcelona, Spain). 2. Experimental 2.2. Sample preparation 2.1. Chemicals and reagents 2.2.1. GC–MS analysis of M1 and M2 One hundred nanograms per millilitre of boldenone (internal 17a-Methyl-5a-androstan-3a,17b-diol (M1), 17a-methyl-5b- standard, ISTD) were added to urine samples (5 mL) which were androstan-3a,17b-diol (M2) and etiocholanolone sulphate were passed through XAD-2 columns previously conditioned with obtained from NMI (Pymble, Australia). 17a-Methyl-5a-andro- 2 mL methanol and 2 mL water. The column was washed with 46 C. Gómez et al. / Steroids 78 (2013) 44–52 2 mL water and the analytes were eluted with 2 mL methanol. The 2.3. LC–MS/MS instrumental conditions methanolic extract was evaporated to dryness under a stream of nitrogen in a water bath at 50 °C and reconstituted with 1 mL of so- Chromatographic separations were carried out on a Waters dium phosphate buffer (0.2 M, pH 7). Enzymatic hydrolysis was Acquity UPLC™ system (Waters Corporation, Milford, MA, USA) performed by adding 30 lLofb-glucuronidase from E.
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