Studies on the in vivo metabolism of the SARM YK11: Identification and characterization of metabolites potentially useful for doping controls. Issue 11 (18th November 2018)

• Record Type: Journal Article
• Authors: Piper, Thomas; Dib, Josef; Putz, Marlen; Fusshöller, Gregor; Pop, Valentin; Lagojda, Andreas; Kuehne, Dirk; Geyer, Hans; Schänzer, Wilhelm; Thevis, Mario
• Is Part Of: Drug testing and analysis. Volume 10:Issue 11/12(2018)
• Page Start: 1646
• Page End: 1656
• Publication Date: 2018-11-18
• Subjects: high resolution–high accuracy mass spectrometry -- human metabolism -- hydrogen isotope ratio mass spectrometry -- SARM -- YK11; Drugs -- Analysis -- Periodicals; Drug testing -- Periodicals; Chemistry, Forensic -- Periodicals; 615.1901
• DOI: 10.1002/dta.2527
• Languages: English
• ISSNs: 1942-7603

Abstract

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. Abstract : Two urinary metabolites (M1 and M2) of the SARM YK11 were identified using hydrogen isotope ratio mass spectrometry combined with high resolution/high accuracy mass spectrometry. Both metabolites were successfully in‐house synthesized and implemented into the currently applied analytical method for the detection of anabolic agents.