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Drug testing and analysis2020; 12(8); 1087-1101; doi: 10.1002/dta.2862

Serum concentrations, pharmacokinetic/pharmacodynamic modeling, and effects of dexamethasone on inflammatory mediators following intravenous and oral administration to exercised horses.

Abstract: Corticosteroids are potent anti-inflammatory drugs and as such are commonly administered to performance and racehorses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics and effects on cortisol and inflammatory mediator concentrations, following intravenous and oral administration to 12 exercised horses. Horses received an intravenous administration of 40 mg of dexamethasone sodium phosphate and 20 mg of dexamethasone tablets with a 4 week washout in between administrations. Blood and urine samples were collected prior to and for up to 96 hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. The concentrations of dexamethasone and eicosanoids were measured using LC-MS/MS and the concentrations from both routes of administration fit simultaneously using a three-compartment pharmacokinetic model. A turnover model with inhibition of K gave an adequate fit to the dexamethasone-cortisol PKPD data. Serum and urine dexamethasone concentrations were at the limit of quantitation at 96 and 48 hours post administration, respectively. The volume of distribution, systemic clearance, and terminal half-life was 0.907 L/kg, 7.89 mL/h/kg, and 1.34 h, respectively. The IC for cortisol suppression was 0.007 ng/mL. Stimulation of dexamethasone treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of inflammatory biomarker production for a prolonged period of time post drug administration. The results of this study suggest that dexamethasone has a prolonged anti-inflammatory effect following intravenous or oral administration to horses.
© 2020 John Wiley & Sons, Ltd.
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Publication Date: 2020-06-22 PubMed ID: 32436346DOI: 10.1002/dta.2862Google Scholar: Lookup
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  • Journal Article

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 paper investigates the effects of dexamethasone, a powerful anti-inflammatory drug, on horses. It focuses specifically on the impact on cortisol levels and inflammatory mediators after administering the drug either orally or intravenously to exercised horses.

Methodology

  • The scientists carried out the study on 12 exercised horses. Each horse received an intravenous injection of dexamethasone, specifically 40 mg dexamethasone sodium phosphate, and 20 mg oral dexamethasone tablets.
  • The researchers enforced a four-week washout period between each administration to eliminate any effects of the previous dosage.
  • They collected blood and urine samples from the horses before and up to 96 hours after administering the dexamethasone. Concentrations of dexamethasone and eicosanoids (molecules involved in inflammation) were measured through these samples using liquid chromatography and tandem mass spectrometry (LC-MS/MS).

Ex Vivo Trial

  • Researchers also conducted an ex vivo trial using the blood samples. These were exposed to lipopolysaccharide or calcium ionophore to artificially induce eicosanoid synthesis, mimicking an inflammatory response.

Pharmacokinetic Analysis

  • They interpreted the pharmacokinetics and effects of the dexamethasone on cortisol and inflammatory mediator concentrations using a three-compartment pharmacokinetic model.
  • They also applied a turnover model with inhibition of K, a parameter referring to drug elimination or transformation, which provided a satisfactory fit to the dexamethasone-cortisol pharmacokinetic/pharmacodynamic (PKPD) data.

Findings

  • The researchers found that serum and urine concentrations of dexamethasone fell to their limit of quantitation at 96 and 48 hours post-administration, respectively.
  • The PK profiles revealed values of distribution volume, systemic clearance, and terminal half-life at 0.907 L/kg, 7.89 mL/h/kg, and 1.34 hours, respectively.
  • The IC for cortisol suppression, referring to the concentration of the drug needed to produce half its maximal effect, was calculated to be 0.007 ng/mL.
  • Furthermore, stimulation of dexamethasone-treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of inflammatory biomarker production for an extended period after drug administration.

Conclusion

  • The study concluded that dexamethasone has a prolonged anti-inflammatory effect when given either intravenously or orally to horses. This suggests that the drug could be beneficial in managing inflammation in performance and racehorses.

Cite This Article

APA
Knych HK, Weiner D, Arthur RM, Baden R, McKemie DS, Kass PH. (2020). Serum concentrations, pharmacokinetic/pharmacodynamic modeling, and effects of dexamethasone on inflammatory mediators following intravenous and oral administration to exercised horses. Drug Test Anal, 12(8), 1087-1101. https://doi.org/10.1002/dta.2862

Publication

Drug testing and analysis
ISSN: 1942-7611
NlmUniqueID: 101483449
Country: England
Language: English
Volume: 12
Issue: 8
Pages: 1087-1101

Researcher Affiliations

Knych, Heather K
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California Davis, CA, USA.
  • Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
Weiner, Daniel
  • Pharmacometrics Consultant.
Arthur, Rick M
  • School of Veterinary Medicine, University of California, Davis, CA, USA.
Baden, Russell
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California Davis, CA, USA.
McKemie, Daniel S
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California Davis, CA, USA.
Kass, Philip H
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA.

MeSH Terms

  • Administration, Intravenous
  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Chromatography, Liquid / methods
  • Dexamethasone / administration & dosage
  • Dexamethasone / analogs & derivatives
  • Dexamethasone / pharmacokinetics
  • Dexamethasone / pharmacology
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / pharmacokinetics
  • Glucocorticoids / pharmacology
  • Half-Life
  • Horses
  • Inflammation / drug therapy
  • Inflammation Mediators / metabolism
  • Inhibitory Concentration 50
  • Models, Biological
  • Tandem Mass Spectrometry / methods
  • Time Factors
  • Tissue Distribution

Grant Funding

  • California Horse Racing Board and the California Department of Food and Agriculture's Equine Medication Monitoring Program

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Citations

This article has been cited 4 times.
  1. Kikuchi M, Nagata SI, Ishige T, Minamijima Y, Hirota KI, Tozaki T, Kakoi H, Kizaki K. Evaluation of the effect of glucocorticoid treatment on adrenocortical functions by monitoring endogenous hydrocortisone in horses.. J Vet Med Sci 2023 Jun 13;85(6):647-652.
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  2. Tou K, Cawley A, Bowen C, Bishop DP, Fu S. Towards Non-Targeted Screening of Lipid Biomarkers for Improved Equine Anti-Doping.. Molecules 2022 Dec 30;28(1).
    doi: 10.3390/molecules28010312pubmed: 36615506google scholar: lookup
  3. Ekstrand C, Pettersson H, Gehring R, Hedeland M, Adolfsson S, Lilliehöök I. Prednisolone in Dogs-Plasma Exposure and White Blood Cell Response.. Front Vet Sci 2021;8:666219.
    doi: 10.3389/fvets.2021.666219pubmed: 34179161google scholar: lookup
  4. Song D, Jusko WJ. Across-species meta-analysis of dexamethasone pharmacokinetics utilizing allometric and scaling modeling approaches.. Biopharm Drug Dispos 2021 May;42(5):191-203.
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