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Home / Equine Research Bank / J Vet Pharmacol Ther / Pharmacokinetics of low-dose methotrexate in horses.
Journal of veterinary pharmacology and therapeutics2020; 43(5); 461-469; doi: 10.1111/jvp.12857

Pharmacokinetics of low-dose methotrexate in horses.

Abstract: This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long-term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10-week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC-MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min  kg (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7-hydroxy-MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg  week may be safe and relevant in horses, although this has yet to be clinically confirmed.
© 2020 John Wiley & Sons Ltd.
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Publication Date: 2020-03-26 PubMed ID: 32216109DOI: 10.1111/jvp.12857Google Scholar: Lookup
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  • Clinical Trial
  • Veterinary
  • 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.

The research article investigates the behavior and tolerance of methotrexate, a potential new immunomodulatory drug, in horses to establish an effective dosage regimen.

Research Design and Process

  • The study revolves around the testing of methotrexate (MTX), a potentially new immunomodulatory drug for horses. Pharmacokinetic behavior as well as the tolerance level of methotrexate was examined to establish a suitable dosing regimen.
  • The experiment involved a total of six horses that received 0.3 mg/kg MTX in a crossover design study. In this design, each horse receives the drug through three different routes – Intravenous, subcutaneous and oral administration – in a rotation allowing the researchers to evaluate the effect of each method within the same subjects.
  • After a 10-week break, the drug was administered again on a weekly basis subcutaneously to half the horses for a period of 3 months. This phase was designed to study any long-term effects or efficacy of the drug.
  • Through both phases of study, MTX and metabolite concentrations were tracked using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS), a highly sensitive and accurate technique for measuring small molecules.

Key Findings

  • The absolute bioavailability of MTX, or the proportion of drug which makes it into circulation, was measured to be 73% following subcutaneous administration, making it the effective route for administration.
  • Less than 1% of the drug reached the horse’s system when given orally, indicating oral administration of the drug isn’t effective in horses.
  • The plasma clearance – the volume of plasma that is completely cleared of the drug per unit time – was measured at 1.54 ml min kg with an extraction ratio of 2%. This indicates that the horse’s body was able to efficiently eliminate the drug from its system.
  • No adverse effects were noted except for a slight temporary increase in liver enzymes (GLDH), which suggests a moderate stress on the liver.
  • Regarding the metabolites of MTX, very low concentrations of 7-hydroxy-MTX were found, while polyglutamated forms, primarily short chains, were detected in red blood cells.
  • Based on the research, it is suggested that a weekly subcutaneous dose of 0.2 mg/kg could be a safe and relevant dosage for horses, but further clinical trials are needed to confirm this.

Cite This Article

APA
Rostang A, Desjardins I, Espana B, Panzuti P, Berny P, Prouillac C, Pin D. (2020). Pharmacokinetics of low-dose methotrexate in horses. J Vet Pharmacol Ther, 43(5), 461-469. https://doi.org/10.1111/jvp.12857

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 43
Issue: 5
Pages: 461-469

Researcher Affiliations

Rostang, Antoine
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.
Desjardins, Isabelle
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.
Espana, Bernadette
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.
Panzuti, Pauline
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.
Berny, Philippe
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.
Prouillac, Caroline
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.
Pin, Didier
  • Université de Lyon, VetAgro Sup, UPSP ICE 'Interactions Cellules Environnement', Marcy l'Etoile, France.

MeSH Terms

  • Animals
  • Area Under Curve
  • Biological Availability
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Half-Life
  • Horses / metabolism
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacokinetics
  • Methotrexate / administration & dosage
  • Methotrexate / pharmacokinetics

Grant Funding

  • ICE Research Unit

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