Pharmacokinetic study of osilodrostat and identification of mono-hydroxylated metabolite in equine plasma for the purpose of doping control.
Abstract: Osilodrostat 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. Methods: Potential 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 (LC/ESI-HRMS). [Correction added on 27 January 2023, after first online publication: In the preceding sentence, "C-HRMS" was changed to "LC/ESI-HRMS" in this version.] 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. Results: Mono-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. Conclusions: For 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.
© 2024 John Wiley & Sons Ltd.
Publication Date: 2024-02-15 PubMed ID: 38355879DOI: 10.1002/rcm.9695Google Scholar: Lookup
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Summary
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The article discusses a study on osilodrostat, a drug used in Cushing’s disease treatment, focusing on its pharmacokinetics and metabolism in horse plasma for doping control in horse racing and equestrian sports. The research was able to identify a metabolite of the drug, establish its elimination profile, and recommend monitoring for doping control.
Research Methodology
- The study used equine plasma samples taken before and after the administration of osilodrostat.
- A differential analysis was performed using Liquid Chromatography Electrospray Ionization High-Resolution Mass Spectrometry (LC/ESI-HRMS) to identify potential metabolites of osilodrostat.
- The drug quantification was achieved using a strong cation exchange solid-phase extraction, and the extracts were analyzed with LC/ESI-Triple Quadrupole Tandem Mass Spectrometry (LC/ESI-QqQ-MS/MS) to establish the drug’s elimination profile.
- Further analysis was completed to study the detectability of the drug and its identified metabolite over a sampling period of 2 weeks.
Study Results
- A mono-hydroxylated metabolite of osilodrostat was identified as the most abundant metabolite in plasma using differential analysis and mass spectrometric interpretations.
- The drug’s elimination profile was successfully established over a 24-hour post-administration period.
- Both the drug and its identified metabolite were detected up to the final sampling point at two weeks with Osilodrostat confirmed up to 8 days post-administration with its reference material using HRMS.
Conclusions and Recommendations
- In doping control, both osilodrostat and its mono-hydroxylated metabolite should be screened due to their extended detection periods of up to two weeks.
- Given the availability of reference material for confirmation in forensic samples, osilodrostat was recommended as the most appropriate monitoring target.
Cite This Article
APA
Ishii H, Ishikawa Y, Mizobe F, Nomura M, Yamanaka T, Tanabe S, Nagata SI, Yamada M, Leung GN.
(2024).
Pharmacokinetic study of osilodrostat and identification of mono-hydroxylated metabolite in equine plasma for the purpose of doping control.
Rapid Commun Mass Spectrom, 38(5), e9695.
https://doi.org/10.1002/rcm.9695 Publication
Researcher Affiliations
- Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.
- Anti-Doping Section, Equine Department, Japan Racing Association, Tokyo, Japan.
- Anti-Doping Section, Equine Department, Japan Racing Association, Tokyo, Japan.
- Anti-Doping Section, Equine Department, Japan Racing Association, Tokyo, Japan.
- Clinical Veterinary Medicine Division, Equine Research Institute, Shimotsuke, Japan.
- Clinical Veterinary Medicine Division, Equine Research Institute, Shimotsuke, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, Utsunomiya, Japan.
- Laboratory of Racing Chemistry, Utsunomiya, Japan.
MeSH Terms
- Animals
- Horses
- Doping in Sports / prevention & control
- Tandem Mass Spectrometry / methods
- Spectrometry, Mass, Electrospray Ionization / methods
- Chromatography, Liquid / methods
- Imidazoles
- Pyridines
Grant Funding
- Japan Racing Association (JRA)
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