Equine metabolism of the growth hormone secretagogue MK-0677 in vitro and in urine and plasma following oral administration.
This study investigated the metabolism of MK-0677 (ibutamoren mesylate), an orally active non-peptide growth hormone secretagogue, in horses to support equine doping control efforts. Researchers conducted both in vitro incubations and in vivo oral administration to two Thoroughbred racehorses, then used liquid chromatography high-resolution mass spectrometry (LC-HRMS) and LC-tandem mass spectrometry to identify and profile metabolites in urine and plasma. Fourteen phase I metabolites were identified in vitro; 13 were subsequently detected in post-administration urine and nine in plasma, along with the parent compound in both matrices. The study found that an O-dealkylated metabolite of MK-0677 showed the longest detection window in both urine and plasma, making it the recommended analytical target for doping control laboratories. Both MK-0677 and this key metabolite were found to be excreted predominantly in unconjugated form. Limitations include the very small sample size (n=2 horses) and the fact that findings are restricted to equine species, meaning results cannot be directly extrapolated to human metabolism or doping detection in human sport.
Why this grade: The study was conducted entirely in horses (n=2 Thoroughbreds) with no human subjects, providing equine-specific metabolic data only.
Ibutamoren mesylate, or MK-0677, is an orally active, nonpeptide growth hormone secretagogue that has been developed to stimulate excretion of endogenous growth hormone. It has been evaluated for the treatment of a range of clinical conditions but is not available therapeutically. Nonetheless, MK-0677 is widely available to purchase online, sold as 'supplement' products. The mode of action and relative ease of purchase make MK-0677 a potential threat with regard to sports doping. The aim of this study was to investigate the metabolism of MK0677 in the horse following in vitro incubation and oral administration to two Thoroughbred racehorses, in order to identify the most appropriate analytical targets for doping control laboratories. Liquid chromatography high resolution mass spectrometry was used for metabolite identification, and subsequently, liquid chromatography-tandem mass spectrometry was used to generate full metabolite profiles for post-administration urine and plasma samples. Fourteen phase I metabolites were identified in vitro; 13 of these were subsequently detected in urine and nine in plasma collected post-administration, alongside the parent compound in both matrices. In both urine and plasma, the longest duration of detection was observed for an O-dealkylated metabolite of MK-0677, and therefore, this would be the best target for the detection of MK-0677 administration. MK-0677 and the O-dealkylated metabolite were found to be excreted largely unconjugated in urine and plasma.
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