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Novel holistic pharmacokinetic model applied to plasma and urine concentrations of 2,5-dihydroxybenzene sulphonate following administrations of calcium dobesilate and etamsylate to exercised horses.
Abstract: Calcium dobesilate (CD) is a synthetic venoactive drug used in veterinary medicine to treat equine navicular disease. Etamsylate is a haemostatic agent used in horses for the treatment of exercise-induced pulmonary haemorrhage. Both etamsylate and CD dissociate in the circulatory system with 2,5-HBSA as the active drug. The aim of the research was to be able to provide detection time (DT) advice from pharmacokinetic (PK) studies in Thoroughbred horses to better inform trainers, and their veterinary surgeons, prescribing these substances for treatment of Thoroughbred racehorses. Two (pilot study) and six (final study) horses were given 28 and 9 repeated dose of CD (3 mg/kg BID) respectively. Two horses were each given a single intravenous (IV) dose of etamsylate (10 mg/kg). Plasma and urine 2,5-HBSA concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The CD pilot study revealed that steady state could be reached with a few days and that 2,5-HBSA in plasma and urine shows instability during storage at -20°C but appears stable at -80°C. A novel holistic non-linear mixed-effects three-compartmental PK model was developed that described both plasma and urine concentrations of 2,5-HBSA, from either CD or etamsylate administration. Typical values for 2,5-HBSA clearance and bioavailability were 2.0 mL/min/kg and 28% respectively. Using the parameters obtained from this PK model, in conjunction with methodology developed by Toutain, afforded a possible screening limit (SL) that can regulate for a DT of 3 days in urine; however, a corresponding SL in plasma would be below current levels of detection. However, it is the responsibility of the individual racing authorities to apply their own risk management with regard to SLs and DTs.
© 2023 John Wiley & Sons Ltd.
Publication Date: 2023-05-31 PubMed ID: 37255256DOI: 10.1111/jvp.13387Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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This research article is about the development of a new pharmacokinetic model to understand and predict the concentration and detection time of the active drug 2,5-HBSA in the plasma and urine of horses. The drug is found in calcium dobesilate and etamsylate, used for treating navicular disease and haemorrhage in horses.
Overview of the Study
The study administered the drug calcium dobesilate (CD) to horses in a pilot and final study. The pilot study had two horses, and the final study had six horses. All horses were given repeated doses of CD. Two horses were also given a single intravenous dose of etamsylate, another source of 2,5-HBSA. The purpose was to investigate how the two substances dissociate into the active substance 2,5-HBSA within the circulatory system. The researchers measured 2,5-HBSA concentrations in plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- The pilot study of CD revealed that stable condition could be achieved within a few days, and 2,5-HBSA in plasma and urine shows instability in storage at -20°C, but stability at -80°C.
- 2,5-HBSA’s clearance and bioavailability were measured, resulting in values of 2.0 mL/min/kg and 28% respectively.
An Innovative Pharmacokinetic Model
An innovative non-linear mixed-effects three-compartmental pharmacokinetic (PK) model was developed as part of this research.
- This model describes both plasma and urine concentrations of 2,5-HBSA, from either CD or etamsylate administration.
- The model was created to provide trainers and veterinary surgeons with accurate detection time advice for the substances.
Implications of the Research
The investigators formulated a potential screening limit (SL) using the parameters derived from the model and a methodology developed by Toutain.
- The SL could adjust for a detection time of three days in urine. However, a corresponding SL in plasma would be below present detection levels.
- Despite the research findings, the responsibility lies with individual racing authorities to manage risk concerning SLs and detection times.
Cite This Article
APA
Paine SW, Harding C, Waller CC, Zemenova J, Viljanto M, Habershon Butcher J, Hincks PR.
(2023).
Novel holistic pharmacokinetic model applied to plasma and urine concentrations of 2,5-dihydroxybenzene sulphonate following administrations of calcium dobesilate and etamsylate to exercised horses.
J Vet Pharmacol Ther.
https://doi.org/10.1111/jvp.13387 Publication
Researcher Affiliations
- School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, UK.
- LGC Ltd, Cambridgeshire, UK.
- LGC Ltd, Cambridgeshire, UK.
- LGC Ltd, Cambridgeshire, UK.
- LGC Ltd, Cambridgeshire, UK.
- British Horse Racing Authority, London, UK.
- LGC Ltd, Cambridgeshire, UK.
Grant Funding
- British Horse Racing Authority
References
This article includes 9 references
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- Russell C, Gray B, Wilkinson S, Woodward K. The detection and confirmation of ethamsylate in equine plasma using LC-MS/MS. In: Proceedings of the 16th International Conference of Racing Analysts and Veterinarians, Tokyo, p. 262-266.
- Segura D, Monreal L, Perez-Pujol S, Alonso A, Diaz-Ricart M, Brugues R, Ordinas A, Escolar G. Effects of etamsylate on equine platelets. In Vitro and In Vivo Studies. Veterinary Journal 174, 325-329.
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- Toutain PL, Lassourd V. Pharmacokinetic/pharmacodynamic approach to assess irrelevant plasma or urine drug concentrations in postcompetition samples for drug control in the horse. Equine Veterinary Journal 34, 242-249.
Citations
This article has been cited 1 times.- Harding C, Viljanto M, Hincks P, Habershon-Butcher J, Paine SW. Plasma and Urine Pharmacokinetics of Long-Acting Injectable Omeprazole Following Intramuscular Administrations to Healthy Thoroughbred Horses. J Vet Pharmacol Ther 2025 May;48(3):155-162.
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