Generic approach for the discovery of drug metabolites in horses based on data-dependent acquisition by liquid chromatography high-resolution mass spectrometry and its applications to pharmacokinetic study of daprodustat

Ishii, Hideaki; Shibuya, Mariko; Kusano, Kanichi; Sone, Yu; Kamiya, Takahiro; Wakuno, Ai; Ito, Hideki; Miyata, Kenji; Sato, Fumio; Kuroda, Taisuke; Yamada, Masayuki; Leung, Gary N. W.

doi:10.1007/s00216-022-04347-2

Cited by 3 publications

(1 citation statement)

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“…The authors previously reported a generic nontargeted methodology for the discovery of drug metabolites in equine based on the differential analysis of HRMS data obtained from pre-and postadministration samples. [11][12][13][14][15][16][17][18][19][20][21][22][23] In this study, we applied the same methodology to look for potential drug metabolites of osilodrostat.…”

Section: Identification Of Metabolites In Equine Plasmamentioning

confidence: 99%

Pharmacokinetic study of osilodrostat and identification of mono‐hydroxylated metabolite in equine plasma for the purpose of doping control

Ishii,

Ishikawa,

Mizobe

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleOsilodrostat is an inhibitor of 11‐beta‐hydroxylase (CYP11B) and is used for the treatment of Cushing's disease but also categorized as an anabolic agent. The use of osilodrostat is prohibited in horseracing and equestrian sports. To the best of our knowledge, this is the first metabolic study of osilodrostat in equine plasma.MethodsPotential metabolites of osilodrostat were identified by differential analysis using data acquired from pre‐ and post‐administration plasma samples after protein precipitation with liquid chromatography electrospray ionization high‐resolution mass spectrometry (C–HRMS). For quantification of osilodrostat, a strong cation exchange solid‐phase extraction was employed, and the extracts were analyzed using LC/ESI–triple quadrupole tandem mass spectrometry (LC/ESI–QqQ‐MS/MS) to establish its elimination profile. Such extracts were further analyzed using LC/ESI–HRMS to investigate the detectability of osilodrostat and its identified mono‐hydroxylated metabolite over a 2‐week sampling period.ResultsMono‐hydroxylated osilodrostat was identified based on the differential analysis and mass spectrometric interpretations, and it was found to be the most abundant metabolite in plasma. Elimination profile of osilodrostat in plasma was successfully established over the 24‐h post‐administration period. Both osilodrostat and its mono‐hydroxylated metabolite were detected up to the last sampling point at 2 weeks using HRMS, and osilodrostat could be confirmed up to 8‐day post‐administration with its reference material using HRMS as well.ConclusionsFor doping control, screening of both the parent drug osilodrostat and its mono‐hydroxylated metabolite in equine plasma would be recommended due to their extended detection windows of up to 2 weeks. Given the availability of reference material for potential confirmation in forensic samples, osilodrostat is considered the most appropriate monitoring target.

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