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

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 (5ß-19-nor-pregnane-3α,17ß,20-triol and 5ß-19-nor-pregnane-3α,17ß-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.

Pharmacokinetics, tissue distribution, and excretion of nomegestrol acetate in female rats.

Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-norprogesterone, is an orally active drug with a strong affinity for the progesterone receptor. NOMAC inhibits ovulation and is devoid of undesirable androgenic and estrogenic activities. The aim of this study was to evaluate the pharmacokinetics, tissue distribution, and excretion of NOMAC in female rats. Sprague-Dawley female rats were orally administered a single dose of NOMAC (10, 20 or 40 mg/kg) and drug plasma concentrations at different times were determined by RP-HPLC. Tissue distribution at 1, 2, and 4 h and excretion of NOMAC into bile, urine, and feces after dosing were investigated. The results showed that NOMAC was rapidly absorbed after oral administration, with [Formula: see text] of 1-2 h. The plasma concentration-time curves were fitted in a two-compartment model. The exposure to NOMAC ([Formula: see text] and [Formula: see text]) increased dose proportionally from 10 to 40 mg/kg. The average CL and [Formula: see text] were 5.58 L/(h·kg) and 10.8 h, respectively. The highest concentrations of NOMAC in ovary, liver, kidney, lung, heart, brain, spleen, muscle, and uterus were observed at 2 h, whereas the highest concentrations in stomach, pituitary, and hypothalamus appeared at 1 h. The total cumulative excretion of NOMAC in feces (0-72 h), urine (0-72 h), and bile (0-48 h) was ~1.06, 0.03, and 0.08 % of the oral administered dose, respectively. This study indicated that NOMAC had a widespread distribution in tissues, including ovary, pituitary, and hypothalamus, which are main target tissues where NOMAC inhibits ovulation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation was found in the drug elimination; however, it did not significantly affect [Formula: see text].