Metabolic profiles of MK-3984 (SARM) in zebrafish using Ultra High Performance liquid chromatography Q Extractive HF Hybrid Quadrupole Orbitrap mass spectrometry (UPLC-QE-HF-MS) for doping control

Abstract

In this study, the metabolic profiles of MK-3984, a selective androgen receptor modulator (SARM) targeting muscle and bone tissues, were comprehensively investigated for the first time using Quadrupole Orbitrap LC-MS/MS in a zebrafish model. The analysis revealed 82 metabolites (M1-M82) and identified 12 distinct metabolic pathways.Phase I metabolism was predominantly characterized by reductive defluorination, while phase II metabolism primarily involved cysteinylation and sulfation. Notably, this study first reported the characteristic neutral losses (87 and 129 Da) associated with cysteinylated and N-acetylated-cysteinylated metabolites in negative ion mode. Three key metabolites-M1 (reductive defluorinated metabolite), M28 (reductive defluorinated, monohydroxylated and sulfated metabolite), and M55 (reductive defluorinated, monohydroxylated and cysteinylated metabolite) were identified as potential biomarkers for monitoring MK-3984 abuse. These findings provide valuable insights into the metabolic fate of MK-3984 and establish a foundation for its detection in anti-doping controls.