Equine metabolic investigation of the phosphodiesterase-4 inhibitor ibudilast as a potential performance enhancer.
Abstract: Phosphodiesterase 4 (PDE4) inhibitors are a newer class of drugs that induce bronchodilation and have anti-inflammatory effects, making them susceptible to misuse as performance enhancers in competitive sports. Methods: This study explores the metabolic conversion of PDE4 inhibitor ibudilast in thoroughbred horses after oral administration and in vitro using equine liver microsomes and Cunninghamella elegans. A liquid chromatography-high resolution mass spectrometry method was used to postulate the plausible structures of the detected metabolites. Results: A total of 20 in vivo metabolites were identified under experimental conditions, including 12 Phase I and 8 Phase II conjugated metabolites. Phase I metabolites were predominantly formed through hydroxylation (mono-, di-, and tri-hydroxylation). Demethylated metabolites were also identified during this investigation. Additionally, the research detected Phase II metabolites conjugated with glucuronic and sulfonic acids. Conclusions: The data presented here can assist in detecting the PDE4 inhibitor ibudilast and uncover its illicit use in competitive sports.
© 2024 John Wiley & Sons Ltd.
Publication Date: 2024-09-23 PubMed ID: 39307998DOI: 10.1002/rcm.9916Google Scholar: Lookup
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Summary
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The study investigates how a drug known as ibudilast, which falls under the class of phosphodiesterase 4 (PDE4) inhibitors, is metabolized in thoroughbred horses. The findings of this study can potentially help in detecting illicit use of this drug in competitive sports.
Research Methods
- The researchers focused on the metabolic conversion of ibudilast, a PDE4 inhibitor, in thoroughbred horses. They used various methods including oral administration to the horses and in vitro testing using horse liver microsomes and an organism known as Cunninghamella elegans.
- A method called liquid chromatography high-resolution mass spectrometry was implemented. This method helped the researchers to hypothesize the potential structures of the detected metabolites of the drug.
Research Findings
- Based on the analysis, a total of 20 unique metabolites were generated under the experimental conditions. Among these 20 compounds, there were 12 Phase I and 8 Phase II metabolites.
- The Phase I metabolites were mainly created through hydroxylation, which includes mono-hydroxylation, di-hydroxylation, and tri-hydroxylation.
- The experiment also identified demethylated metabolites, which involve the subtraction of a methyl group.
- In addition to these, Phase II metabolites were identified, which were specifically conjugated with glucuronic and sulfonic acids. Conjugation is a phase of drug metabolism where the body makes the drug or its metabolites more soluble in water for easier elimination.
Research Conclusions
- The researchers concluded that the data obtained from this study could potentially aid in detecting ibudilast, a PDE4 inhibitor, in sport horse doping events.
- Identifying the metabolic products of ibudilast not only helps detect its presence but also provides additional insights into how the drug is processed in horse bodies, which could be vital in situations of misusage in competitive sports.
Cite This Article
APA
Philip M, Kal AKK, Subhahar MB, Karatt TK, Graiban FM, Ajeebsanu MM, Joseph M, Jose SV.
(2024).
Equine metabolic investigation of the phosphodiesterase-4 inhibitor ibudilast as a potential performance enhancer.
Rapid Commun Mass Spectrom, 38(23), e9916.
https://doi.org/10.1002/rcm.9916 Publication
Researcher Affiliations
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Department of Bacteriology, Diagnostic Section, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Department of Bacteriology, Diagnostic Section, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
MeSH Terms
- Animals
- Horses
- Phosphodiesterase 4 Inhibitors / metabolism
- Phosphodiesterase 4 Inhibitors / chemistry
- Phosphodiesterase 4 Inhibitors / pharmacology
- Pyridines / metabolism
- Pyridines / chemistry
- Pyridines / pharmacology
- Pyridines / analysis
- Microsomes, Liver / metabolism
- Microsomes, Liver / drug effects
- Performance-Enhancing Substances / metabolism
- Performance-Enhancing Substances / chemistry
- Performance-Enhancing Substances / pharmacology
- Doping in Sports
- Indolizines
- Pyrazoles
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