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Drug testing and analysis2024; doi: 10.1002/dta.3822

Investigation Into the Equine Metabolism of Phosphodiesterase-4 Inhibitor Roflumilast for Potential Doping Control.

Abstract: The phosphodiesterase 4 (PDE4) inhibitors constitute a relatively modern class of medications that are known for inducing bronchodilation and exhibiting anti-inflammatory properties within the body. Due to these properties, there is concern regarding their potential misuse as performance-enhancing substances in competitive sports. This study delves into the metabolic conversion of roflumilast in thoroughbred horses following oral administration and in vitro experimentation using equine liver microsomes and Cunninghamella elegans. High-performance liquid chromatography coupled with a Q Exactive Orbitrap mass spectrometer (HPLC-HRMS) was employed for analysis. The investigation identified 10 metabolites of roflumilast, including six phase I and four phase II metabolites from in vivo studies, and 11 metabolites from in vitro studies, consisting of eight phase I and three phase II metabolites. The identified biotransformation products encompassed processes such as hydroxylation, chlorine substitution, methylation, N-oxide formation, and even the dissociation of methylenecyclopropane and difluoromethane. Furthermore, the study identified three glucuronic acid and one sulfonic acid conjugated phase II metabolites of the investigated drug candidate. The aforementioned findings contribute to the detection and comprehension of the unauthorized utilization of roflumilast in equestrian sports.
© 2024 John Wiley & Sons Ltd.
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Publication Date: 2024-11-17 PubMed ID: 39551487DOI: 10.1002/dta.3822Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates how the drug roflumilast, a type of medication known as a phosphodiesterase 4 inhibitor, is metabolized in thoroughbred horses, aiming to better understand its potential misuse in competitive horse racing.

Overview of Phosphodiesterase 4 Inhibitors

  • Phosphodiesterase 4 (PDE4) inhibitors are a class of drugs known for their bronchodilation and anti-inflammatory effects.
  • Because of these effects, there is potential for these drugs to be misused to enhance performance in sports, particularly in equestrian sports.

Investigation of Roflumilast Metabolism

  • The research focuses on the metabolic conversion of one specific PDE4 inhibitor, roflumilast, in thoroughbred horses.
  • This was studied both in vivo – through oral administration of the drug to the horses – and in vitro, using equine liver microsomes and a fungus called Cunninghamella elegans that is often used in drug metabolism studies.

Analysis Technique

  • The researchers used an analytical technique called high-performance liquid chromatography coupled with a Q Exactive Orbitrap mass spectrometer (HPLC-HRMS) to study the metabolic products of roflumilast.

Findings

  • The study identified a total of 10 metabolites of roflumilast from the in vivo studies and an additional 11 metabolites from the in vitro studies. These include both phase I and phase II metabolites, which refer to different stages in the body’s processing of the drug.
  • The identified metabolites showed a variety of transformations, including hydroxylation, chlorine substitution, methylation, N-oxide formation, and dissociation of methylenecyclopropane and difluoromethane.
  • The study also identified conjugated phase II metabolites – compounds created when the body attaches certain chemicals to the drug to make it easier to excrete. These included three glucuronic acid conjugates and one sulfonic acid conjugate.

Implications

  • The findings of this study contribute to our understanding of how roflumilast is metabolized in horses, which can aid in detecting its unauthorized use in horse racing.
  • Knowing the metabolic products of roflumilast can help in designing drug tests to detect its use.

Cite This Article

APA
Philip M, Karakka Kal AK, Subhahar MB, Karatt TK, Graiban FM, Ajeebsanu MM, Joseph M, Jose SV. (2024). Investigation Into the Equine Metabolism of Phosphodiesterase-4 Inhibitor Roflumilast for Potential Doping Control. Drug Test Anal. https://doi.org/10.1002/dta.3822

Publication

Drug testing and analysis
ISSN: 1942-7611
NlmUniqueID: 101483449
Country: England
Language: English

Researcher Affiliations

Philip, Moses
  • Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
Karakka Kal, Abdul Khader
  • Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
Subhahar, Michael Benedict
  • Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
Karatt, Tajudheen K
  • Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
Graiban, Fatma Mohammed
  • Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
Ajeebsanu, Meleparappil Muhammed
  • Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
Joseph, Marina
  • Department of Bacteriology, Diagnostic Section, Central Veterinary Research Laboratory, Dubai, UAE.
Jose, Shantymol V
  • Department of Bacteriology, Diagnostic Section, Central Veterinary Research Laboratory, Dubai, UAE.

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