Investigation of the metabolism of the selective androgen receptor modulator LGD‐4033 in equine urine, plasma and hair following oral administration

This paper describes the studies of the in vitro biotransformation of two selective androgen receptor modulators (SARMs), namely, RAD140 and S‐23, and the in vivo metabolism of RAD140 in horses using ultra‐high performance liquid chromatography–high resolution mass spectrometry. in vitro metabolic studies of RAD140 and S‐23 were performed using homogenised horse liver. The more prominent in vitro biotransformation pathways for RAD140 included hydrolysis, hydroxylation, glucuronidation and sulfation. Metabolic pathways for S‐23 were similar to those for other arylpropionamide‐based SARMs. The administration study of RAD140 was carried out using three retired thoroughbred geldings. RAD140 and the majority of the identified in vitro metabolites were detected in post‐administration urine samples. For controlling the misuse of RAD140 in horses, RAD140 and its metabolite in sulfate form gave the longest detection time in hydrolysed urine and could be detected for up to 6 days post‐administration. In plasma, RAD140 itself gave the longest detection time of up to 13 days. Apart from RAD140 glucuronide, the metabolites of RAD140 described herein have never been reported before.

Section: Introductionmentioning

confidence: 99%

Metabolic studies of selective androgen receptor modulators RAD140 and S‐23 in horses

Wong

Choi

et al. 2020

“…To date, metabolism studies in the horse have included the characterisation of in vitro produced metabolites of the aryl‐propionamide SARMs S24 and S4 (andarine), 16 as well as the characterisation of urinary metabolites of the SARMs S1, andarine and ostarine following intravenous (IV) administration 17 . The urinary and plasma metabolites of the pyrrolidine–benzonitrile SARM LGD‐4033 have also been reported following IV 18 and oral administration 19 . The latter study also reported the detection of a mono‐hydroxylated metabolite in post‐administration hair samples.…”

Section: Introductionmentioning

confidence: 99%

“…The latter study also reported the detection of a mono‐hydroxylated metabolite in post‐administration hair samples. The metabolite profiles and target analytes can differ dependent on the different routes of administration, as was demonstrated by a comparison of IV and oral results 19 . With SARMs being developed to display increased oral bioavailability and being sold online mainly as powders and capsules for oral dosing, the investigation of the metabolites observed following oral administration is important.…”

Section: Introductionmentioning

confidence: 99%

Equine metabolism of the selective androgen receptor modulator AC‐262536 in vitro and in urine, plasma and hair following oral administration

Cutler¹,

Viljanto²,

Taylor³

et al. 2020

Self Cite

AC‐262536 is one of a number of selective androgen receptor modulators that are being developed by the pharmaceutical industry for treatment of a range of clinical conditions including androgen replacement therapy. Though not available therapeutically, selective androgen receptor modulators are widely available to purchase online as (illegal) supplement products. The growth‐ and bone‐promoting effects, along with fewer associated negative side effects compared with anabolic–androgenic steroids, make these compounds a significant threat with regard to doping control in sport. The aim of this study was to investigate the metabolism of AC‐262536 in the horse following in vitro incubation and oral administration to two Thoroughbred horses, in order to identify the most appropriate analytical targets for doping control laboratories. Urine, plasma and hair samples were collected and analysed for parent drug and metabolites. Liquid chromatography–high‐resolution mass spectrometry was used for in vitro metabolite identification and in urine and plasma samples. Nine phase I metabolites were identified in vitro; four of these were subsequently detected in urine and three in plasma, alongside the parent compound in both matrices. In both urine and plasma samples, the longest detection window was observed for an epimer of the parent compound, which is suggested as the best target for detection of AC‐262536 administration. AC‐262536 and metabolites were found to be primarily glucuronide conjugates in both urine and plasma. Liquid chromatography–tandem mass spectrometry analysis of post‐administration hair samples indicated incorporation of parent AC‐262536 into the hair following oral administration. No metabolites were detected in the hair.

“…Due to possible long‐term detection in hair, valuable methods are established to differentiate food contamination from clenbuterol abuse 10 and to identify administered intact compounds, for example, testosterone esters in connection to elevated T/E ratio in urine 11 . With regard to SARMs, only few studies investigated their incorporation in the hair matrix, among them LGD‐4033, SARMs S4 and S22 12–14 …”

Section: Introductionmentioning

confidence: 99%

“…11 With regard to SARMs, only few studies investigated their incorporation in the hair matrix, among them LGD-4033, SARMs S4 and S22. [12][13][14] Aim of the present study was the elucidation of the in vivo metabolism of GSK2881078 to identify metabolites as potential targets for doping analysis. After oral administration of GSK2881078 by one healthy volunteer, urine samples were collected up to 42 days post administration.…”

Section: Introductionmentioning

confidence: 99%

Detection of the selective androgen receptor modulator GSK2881078 and metabolites in urine and hair after single oral administration

Rading¹,

Anielski²,

Thieme³

et al. 2020

Hair and urine concentrations of the nonsteroidal selective androgen receptor modulator GSK2881078 were examined following single oral administration to investigate its hair incorporation and estimate the general suitability of hair testing for selected androgen receptor modulators. Hair segments were collected following a single dose of 1.5 mg GSK2881078 by repeated shaving of scalp hair at Week 0 (blank), Week 1 (representing the pre-application period), Week 3 (ideally focusing the time of incorporation), and Weeks 5 and 9 (post-administration period). The intact compound and various (at least 4) hydroxy-metabolites exhibited similar elimination profiles. The peak urinary concentration (approximately 920 pg/ml) was observed after 8 h and is reduced to the detection limit (2 pg/ml) on Day 42 following administration of 760 μg GSK2881078. Correspondingly, hair concentrations of GSK2881078 (intact compound only) following a single oral dose of 1.5 mg GSK2881078 reached a peak concentration of 1.7 pg/mg in the segments collected 3 weeks post administration, representing the time of ingestion. The concentration rapidly declined to trace amounts of 0.7 (Week 5) and 0.2 pg/mg (Week 9), respectively. In conclusion, measurement of the intact compound GSK2881078 is feasible for both urine and hair analysis. However, concentrations in hair after single oral administration are in the low pg/mg range and can only be detected, if the segments cover the administration period.