Pharmacokinetics of low‐dose methotrexate in horses. Issue 5 (26th March 2020)

• Record Type: Journal Article
• Authors: Rostang, Antoine; Desjardins, Isabelle; Espana, Bernadette; Panzuti, Pauline; Berny, Philippe; Prouillac, Caroline; Pin, Didier
• Is Part Of: Journal of veterinary pharmacology and therapeutics. Volume 43:Issue 5(2020)
• Page Start: 461
• Page End: 469
• Publication Date: 2020-03-26
• Subjects: bioavailability -- clearance -- horse -- immunomodulator -- tolerance; Veterinary pharmacology -- Periodicals; Therapeutics -- Periodicals; 636.0895105
• DOI: 10.1111/jvp.12857
• Languages: English
• ISSNs: 0140-7783

Abstract

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 −1 kg −1 (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 −1 week −1 may be safe and relevant in horses, although this has yet to be clinically confirmed.