Combination of carbon isotope ratio with hydrogen isotope ratio determinations in sports drug testing

Piper, Thomas; Emery, Caroline M.; Thomas, Andreas; Saugy, Martial; Thevis, Mario

doi:10.1007/s00216-013-6949-3

Cited by 38 publications

(58 citation statements)

References 37 publications

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“…[21][22][23] The results are depicted in Figure 7 and clearly demonstrate the potential of EPIA as a long term metabolite for T administration. [21][22][23] The results are depicted in Figure 7 and clearly demonstrate the potential of EPIA as a long term metabolite for T administration.…”

Section: Excretion Studiesmentioning

confidence: 79%

“…[20][21][22][23][24] The HPLC clean-up was performed on an Agilent 1100 HPLC system (Waldbronn, Germany) equipped with a XBridge TM Shield RP18 5 mm (4.6 x 250 mm) column protected with a XBridge TM Shield RP18 5 mm (4.6 x 20 mm) guard column purchased from Waters (Eschborn, Germany). [20][21][22][23][24] The HPLC clean-up was performed on an Agilent 1100 HPLC system (Waldbronn, Germany) equipped with a XBridge TM Shield RP18 5 mm (4.6 x 250 mm) column protected with a XBridge TM Shield RP18 5 mm (4.6 x 20 mm) guard column purchased from Waters (Eschborn, Germany).…”

Section: Sample Preparation For Hir Determinationsmentioning

confidence: 99%

“…[25] After evaporation to dryness the sample was reconstituted in 200 μL of ethyl acetate and transferred into an autosampler vial for IRMS determinations. [22,23] Gas chromatography-isotope ratio mass spectrometry setup Detection of deuterium-labelled metabolites was conducted on a Delta V Plus isotope ratio mass spectrometer coupled to a Trace GC 1310 gas chromatograph equipped with a TriPlusRSG Autosampler (Thermo Fisher, Bremen, Germany). [16] Sample preparation for CIR determinations All samples re-analyzed for CIR were prepared according to published protocols using 10 mL of each urine.…”

Section: Sample Preparation For Hir Determinationsmentioning

confidence: 99%

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Genotype‐dependent metabolism of exogenous testosterone – new biomarkers result in prolonged detectability

Piper

Schänzer

Thevis

2016

Drug Testing and Analysis

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Testosterone (T) misuse still represents a major problem in sports drug testing. Many strategies have been developed and applied to routine doping controls in recent years to enable both to identify suspicious samples in initial testing procedures and to confirm the exogenous origin of urinary T by means of carbon isotope ratio (CIR) determinations. Depending on the tested individual's genotype of UGT2B17, significantly different amounts of T are glucuronidated and excreted, which results in unaffected T/epitestosterone ratios after T misuse in those subjects with the deletion/deletion polymorphism (del/del). The aim of this study was to investigate differences in metabolic pathways of orally administered T between persons of del/del and insertion/insertion (ins/ins) genetic polymorphism. Therefore, a recently established method using hydrogen isotope ratios together with high-resolution and high-accuracy mass spectrometry was applied after administration of deuterated T to n = 4 subjects including both genotypes. Participants collected urine specimens directly before and for up to 8 days after the application. Urine aliquots were prepared to yield unconjugated, glucuronidated, and sulphoconjugated fractions of urinary steroids. Besides the significant difference in the excretion of T-glucuronide, all measured metabolites varied rather on an individual basis than due to a genotype difference. New T metabolites (both methylated and de-methylated) were detected and investigated regarding their potential to enhance the screening for T misuse. Sulphoconjugated epiandrosterone was further identified as the biomarker allowing for a prolonged retrospective detection of T misuse by means of CIR determinations for up to 5 days compared to 1 day if currently applied sports drug testing procedures were used. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Excretion Studiesmentioning

confidence: 79%

Section: Sample Preparation For Hir Determinationsmentioning

confidence: 99%

Section: Sample Preparation For Hir Determinationsmentioning

confidence: 99%

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Genotype‐dependent metabolism of exogenous testosterone – new biomarkers result in prolonged detectability

Piper

Schänzer

Thevis

2016

Drug Testing and Analysis

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“…[14][15][16][17] In brief, samples were applied to a preconditioned solid-phase extraction (SPE) cartridge, washed with water, and eluted with methanol. [14][15][16][17] In brief, samples were applied to a preconditioned solid-phase extraction (SPE) cartridge, washed with water, and eluted with methanol.…”

Section: Elimination Studiesmentioning

confidence: 99%

Studies on the in vivo metabolism of the SARM YK11: Identification and characterization of metabolites potentially useful for doping controls

Piper

Dib

Putz

et al. 2018

Drug Testing and Analysis

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A steroidal compound was recently detected in a seized black market product and was identified as (17α,20E)-17,20-[(1-methoxyethylidene) bis (oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11). This compound is described to possess selective androgen receptor modulator-and myostatin inhibitor-like properties. As YK11 is an experimental drug candidate and a non-approved substance for humans, scientific data on its metabolism is scarce. Due to its steroidal backbone and the arguably labile orthoester-derived moiety positioned at the D-ring, substantial metabolic conversion in vivo was anticipated. To unambiguously detect urinary metabolites of YK11, an elimination study with six-fold deuterated YK11 was conducted. Post-administration specimens were analyzed using hydrogen isotope ratio mass spectrometry coupled to single quadrupole mass spectrometry to identify metabolites alongside basic mass spectrometric data. Further characterization of those metabolites relevant to sports drug testing was accomplished using gas chromatography-high resolution-high accuracy mass spectrometry. Fourteen deuterated urinary metabolites were detected comprising unconjugated, glucuronidated, and sulfoconjugated metabolites. As expected, no intact YK11 was observed in the elimination study urine samples. While the unconjugated metabolites disappeared within 24 hours post-administration, both glucuronidated and sulfated metabolites were traceable for more than 48 hours. The chemical structures of the two most promising glucuronidated metabolites (5β-19-nor-pregnane-3α,17β,20-triol and 5β-19-norpregnane-3α,17β-diol-20-one) were verified by in-house synthesis of both metabolites and confirmed by nuclear magnetic resonance analysis. In order to elucidate their potential in sports drug testing, both were successfully implemented into the currently applied analytical method for the detection of anabolic agents. KEYWORDS high resolution-high accuracy mass spectrometry, human metabolism, hydrogen isotope ratio mass spectrometry, SARM, YK11

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“…A limitation of this methodology is the recent identification of a small minority of seized T product samples with nondepleted carbon isotope ratio [83] . The complementary development of hydrogen ion ratio MS further refines the ability to distinguish between endogenous and exogenous steroids in such cases [84,85] .…”

mentioning

confidence: 99%

Androgens

Iyer¹,

Handelsman²

2016

Frontiers of Hormone Research

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Androgen abuse is the most potent and prevalent form of sports doping detected. It originated from the early years of the Cold War as an epidemic confined to drug cheating within elite power sports. In the decades following the end of the Cold War, it has become disseminated into an endemic based within the illicit drug subcultures serving recreational abusers seeking cosmetic body sculpting effects. Within sports, both direct androgen abuse (administration of androgens), as well as indirect androgen abuse (administration of nonandrogenic drugs to increase endogenous testosterone), is mostly readily detectable with mass spectrometry-based anti-doping urine tests. The ongoing temptation of fame and fortune and the effectiveness of androgen abuse in power sports continue to entice cheating via renewed approaches aiming to exploit androgens. These require ongoing vigilance, inventiveness in anti-doping science, and targeting coaches as well as athletes in order to build resilience against doping and maintain fairness in elite sport. The challenge of androgen abuse in the community among recreational abusers has barely been recognized and effective approaches remain to be developed.

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Combination of carbon isotope ratio with hydrogen isotope ratio determinations in sports drug testing

Cited by 38 publications

References 37 publications

Genotype‐dependent metabolism of exogenous testosterone – new biomarkers result in prolonged detectability

Genotype‐dependent metabolism of exogenous testosterone – new biomarkers result in prolonged detectability

Studies on the in vivo metabolism of the SARM YK11: Identification and characterization of metabolites potentially useful for doping controls

Androgens

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