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

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Studies on the in vivo metabolism of the SARM YK11 : Identification and characterization of metabolites potentially useful for doping controls. / Piper, Thomas; Dib, Josef; Putz, Marlen; Fusshöller, Gregor; Pop, Valentin; Lagojda, Andreas; Kuehne, Dirk; Geyer, Hans; Schänzer, Wilhelm; Thevis, Mario.

In: Drug testing and analysis, Vol. 10, No. 11-12, 31.10.2018, p. 1646-1656.

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@article{9146ea578bac44fa8f0408835cec446a,
title = "Studies on the in vivo metabolism of the SARM YK11: Identification and characterization of metabolites potentially useful for doping controls",
abstract = "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-nor-pregnane-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 = "Journal Article",
author = "Thomas Piper and Josef Dib and Marlen Putz and Gregor Fussh{\"o}ller and Valentin Pop and Andreas Lagojda and Dirk Kuehne and Hans Geyer and Wilhelm Sch{\"a}nzer and Mario Thevis",
note = "{\circledC} 2018 John Wiley & Sons, Ltd.",
year = "2018",
month = "10",
day = "31",
doi = "10.1002/dta.2527",
language = "English",
volume = "10",
pages = "1646--1656",
journal = "Drug testing and analysis",
issn = "1942-7603",
publisher = "John Wiley & Sons, Ltd",
number = "11-12",

}

RIS

TY - JOUR

T1 - Studies on the in vivo metabolism of the SARM YK11

T2 - Identification and characterization of metabolites potentially useful for doping controls

AU - Piper, Thomas

AU - Dib, Josef

AU - Putz, Marlen

AU - Fusshöller, Gregor

AU - Pop, Valentin

AU - Lagojda, Andreas

AU - Kuehne, Dirk

AU - Geyer, Hans

AU - Schänzer, Wilhelm

AU - Thevis, Mario

N1 - © 2018 John Wiley & Sons, Ltd.

PY - 2018/10/31

Y1 - 2018/10/31

N2 - 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-nor-pregnane-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.

AB - 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-nor-pregnane-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.

KW - Journal Article

U2 - 10.1002/dta.2527

DO - 10.1002/dta.2527

M3 - Conference article in journal

VL - 10

SP - 1646

EP - 1656

JO - Drug testing and analysis

JF - Drug testing and analysis

SN - 1942-7603

IS - 11-12

ER -

ID: 3530998