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Journal of veterinary pharmacology and therapeutics2021; 44(5); 733-744; doi: 10.1111/jvp.12991

Kinetic disposition of diazepam and its metabolites after intravenous administration of diazepam in the horse: Relevance for doping control.

Abstract: In horses, the benzodiazepine diazepam (DIA) is used as sedative for pre-medication or as an anxiolytic to facilitate horse examinations. As the sedative effects can also be abused for doping purposes, DIA is prohibited in equine sports. DIA is extensively metabolized to several active metabolites such as nordazepam, temazepam and oxazepam (OXA). For veterinarians, taking into account the detection times of DIA and its active metabolites is needed for minimizing the risk of an anti-doping rule violation. Therefore, a pharmacokinetic study on 6 horses was conducted using a single intravenous (IV) dose of 0.2 mg/kg DIA Plasma and urine samples were collected at specified intervals until 16 and 26 days post-administration, respectively. Samples were analysed by a sensitive liquid chromatography-electrospray ionization/tandem mass spectrometry method. DIA showed a triphasic elimination pattern in the horse. The mean plasma clearance of DIA was 5.9 ml/min/kg, and the plasma elimination half-life in the terminal phase was 19.9 h. Applying the Toutain model approach, an effective plasma concentration of DIA was estimated at 24 ng/ml, and irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were computed to 0.047 and 0.1 ng/ml, respectively. The detection time according to the European Horserace Scientific Liaison Committee (EHSLC), that is the time for which observed DIA plasma concentrations of all investigated horses were below the IPC was 10 days. Using Monte Carlo Simulations, it was estimated that concentrations of DIA in plasma would fall below the IPC 18 days after the DIA administration for 90% of horses. However, in the present study, a single administration of DIA could be detected for 24 days in urine via the presence of OXA, its dominant metabolite.
© 2021 The Authors. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.
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Publication Date: 2021-06-11 PubMed ID: 34115414DOI: 10.1111/jvp.12991Google 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.

The study reveals the metabolic process and excretion time of diazepam, a sedative drug used in horses and its active metabolites, thus aiding in the anti-doping measures in equine sports. The researchers found that, following intravenous administration, diazepam exhibited a triphasic elimination pattern with the main metabolite being oxazepam. Its detection period in urine was up to 24 days post-administration.

Conclusion

The study aimed to provide insights into the pharmacokinetics of diazepam in horses, which is a potent sedative. Diazepam is also a potent substance which can be misused for doping in horse racing. Therefore, understanding its metabolic pathway and detection times is crucial to maintain fair practices in the sport.

  • The study was carried out on six horses who were administered with an intravenous dose of diazepam. Their plasma and urine samples were collected at intervals for up to 16 and 26 days respectively.
  • The researchers observed a triphasic elimination pattern of diazepam in horses, which means the drug was released from their body in three phases.
  • The mean plasma clearance of diazepam was found to be 5.9 ml/min/kg and the terminal phase plasma elimination half-life was around 19.9 hours.
  • Based on the Toutain model approach which is commonly used for determining drug excretion in veterinary medicine, they estimated the effective plasma concentration of diazepam to be at 24 ng/ml.
  • The irrelevant plasma concentration (IPC) – a marker determining the ability to detect the substance – and irrelevant urine concentration (IUC) were computed to be 0.047 and 0.1 ng/ml, respectively.
  • By applying European Horserace Scientific Liaison Committee (EHSLC) standards, which are well-established guidelines for substance detection in horses, the detection time when the diazepam concentration in all the tested horses fell below the IPC – was found to be 10 days.
  • Using Monte Carlo Simulations – a statistical technique used for predicting the probability of different outcomes – it was predicted that diazepam concentrations in plasma would fall below the IPC after 18 days of diazepam administration in 90% of the test subjects.
  • However, the presence of Oxazepam, the dominant metabolite of diazepam, could still be detected in urine even 24 days after administration.

In conclusion, the study threw light on the time frame for the detection of the sedative and its metabolites in blood and urine post-administration, thereby proving useful for doping control measures.

Cite This Article

APA
Schenk I, Machnik M, Broussou D, Meuly A, Roques BB, Lallemand E, Düe M, Röttgen H, Lagershausen H, Toutain PL, Thevis M. (2021). Kinetic disposition of diazepam and its metabolites after intravenous administration of diazepam in the horse: Relevance for doping control. J Vet Pharmacol Ther, 44(5), 733-744. https://doi.org/10.1111/jvp.12991

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 44
Issue: 5
Pages: 733-744

Researcher Affiliations

Schenk, Ina
  • Institute of Biochemistry, Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany.
Machnik, Marc
  • Institute of Biochemistry, Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany.
Broussou, Diane
  • INTHERES, INRAE, ENVT, Université de Toulouse, Toulouse, France.
Meuly, Astrid
  • INTHERES, INRAE, ENVT, Université de Toulouse, Toulouse, France.
Roques, Béatrice B
  • INTHERES, INRAE, ENVT, Université de Toulouse, Toulouse, France.
Lallemand, Elodie
  • INTHERES, INRAE, ENVT, Université de Toulouse, Toulouse, France.
Düe, Michael
  • Cologne, Germany.
Röttgen, Helma
  • Institute of Biochemistry, Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany.
Lagershausen, Henrike
  • German Equestrian Federation, Warendorf, Germany.
Toutain, Pierre-Louis
  • INTHERES, INRAE, ENVT, Université de Toulouse, Toulouse, France.
  • Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK.
Thevis, Mario
  • Institute of Biochemistry, Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany.

MeSH Terms

  • Administration, Intravenous / veterinary
  • Animals
  • Chromatography, Liquid / veterinary
  • Diazepam
  • Doping in Sports
  • Horses
  • Nordazepam

Grant Funding

  • Deutsche Reiterliche Vereinigung

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