Metabolic Pathway of Osilodrostat in Equine Urine Established through High-resolution Mass Spectrometric Characterization for Doping Control.
Abstract: Osilodrostat, used to treat Cushing's disease, exhibits an anabolic effect, leading to its classification as a prohibited substance in horseracing and equestrian sports. This study reports the characterization of osilodrostat metabolites in horse urine and elucidates its metabolic pathways for the first time for doping control purposes. Methods: Osilodrostat was administered nasoesophageally to four thoroughbreds (one gelding and three mares) at a dose of 50 mg each. Potential metabolites were extensively screened via our developed generic approach employing differential analysis to identify metabolites. Specifically, high-resolution mass spectral data were compared between pre- and post-administration samples on the basis of criteria of fold-changes of peak areas and their P values. Potential metabolite candidates were further identified through mass spectral interpretations using product ion scan data. Results: A total of 37 metabolites were identified after comprehensive analysis. Osilodrostat was predominantly metabolized into a mono-hydroxylated form M1c (~40%) alongside osilodrostat glucuronide M2 (~17%). Given their longest detection time (2 weeks after administration) and the identification of several conjugates of osilodrostat and M1c, including a novel conjugate of riburonic acid, we recommend monitoring both osilodrostat and M1c after hydrolysis during the screening stage. However, only osilodrostat can be used for confirmation because of the availability of a reference material. Conclusions: It is advisable to screen for both osilodrostat and its mono-hydroxylated metabolite M1c to effectively monitor horse urine for the potential misuse or abuse of osilodrostat. For suspicious samples, confirmation of osilodrostat using its reference material is required.
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Publication Date: 2024-09-05 PubMed ID: 39238378DOI: 10.2174/0113892002325954240903062440Google Scholar: Lookup
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Summary
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This research article investigates osilodrostat’s metabolism in horses, a drug used to treat Cushing’s disease but prohibited in horse racing due to its anabolic effects. A total of 37 metabolites of the drug were identified, with two major forms, M1c and M2, suggested as the primary targets for doping control.
Experiment Procedure
- The study began with nasoesophageal administration of osilodrostat to four thoroughbreds, with each horse receiving a 50 mg dose.
- The researchers then used a generic approach developed internally for comprehensive screening of potential metabolites. This approach entailed differential analysis to identify metabolites.
- High-resolution mass spectral data were compared from before and after drug administration, with criteria being changes in peak areas and their P values.
- For further identification of potential metabolite candidates, mass spectral interpretations were used with the help of product ion scan data.
Findings
- The research identified a total of 37 metabolites after comprehensive analysis.
- Predominantly, osilodrostat was metabolized into a mono-hydroxylated form, M1c, which was around 40% of the metabolites, and osilodrostat glucuronide M2, about 17%.
- Osilodrostat and M1c showed the longest detection time, up to 2 weeks after administration, indicating their significance as potential targets for doping detection.
- The analysis also revealed several conjugates of osilodrostat and M1c, including a novel conjugate of riburonic acid.
Recommendations
- According to these findings, it’s advisable to screen for both osilodrostat and its mono-hydroxylated metabolite M1c to effectively monitor horse urine for potential misuse or abuse of osilodrostat.
- Despite the considerable presence of M1c in urine, only screening for osilodrostat can be used for confirmation due to the availability of a reference material.
- In cases of suspicious samples, a confirmation of osilodrostat using its reference material is required for a conclusive result.
Cite This Article
APA
Ishii H, Shigematsu R, Takemoto S, Ishikawa Y, Mizobe F, Nomura M, Arima D, Kunii H, Yuasa R, Yamanaka T, Tanabe S, Nagata SI, Yamada M, Leung GN.
(2024).
Metabolic Pathway of Osilodrostat in Equine Urine Established through High-resolution Mass Spectrometric Characterization for Doping Control.
Curr Drug Metab.
https://doi.org/10.2174/0113892002325954240903062440 Publication
Researcher Affiliations
- Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, 320-0851, Japan.
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, 320-0851, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, 320-0851, Japan.
- Anti-Doping Section, Equine Department, Japan Racing Association, 6-11-1 Roppongi, Minato-ku, Tokyo, 105-0003, Japan.
- Anti-Doping Section, Equine Department, Japan Racing Association, 6-11-1 Roppongi, Minato-ku, Tokyo, 105-0003, Japan.
- Anti-Doping Section, Equine Department, Japan Racing Association, 6-11-1 Roppongi, Minato-ku, Tokyo, 105-0003, Japan.
- Equine Veterinary Clinic, Horse Racing School, Japan Racing Association, 835-1 Ne Shiroi city, Chiba, Japan, 270-1431, Japan.
- Equine Veterinary Clinic, Horse Racing School, Japan Racing Association, 835-1 Ne Shiroi city, Chiba, Japan, 270-1431, Japan.
- Equine Veterinary Clinic, Horse Racing School, Japan Racing Association, 835-1 Ne Shiroi city, Chiba, Japan, 270-1431, Japan.
- Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, 1400-4 Shiba, Shimotsuke, Tochigi, 329-0412, Japan.
- Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, 1400-4 Shiba, Shimotsuke, Tochigi, 329-0412, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, 320-0851, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, 320-0851, Japan.
- Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, 320-0851, Japan.
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