Pharmacokinetics and anti‐inflammatory effects of flunixin meglumine as a sole agent and in combination with phenylbutazone in exercised Thoroughbred horses

Abstract

Background: Flunixin meglumine (FM) and phenylbutazone (PBZ) are potent anti-inflammatory agents and as such their potential to mask injuries that would otherwise keep a horse from training or racing is concerning. A common practice in racetrack medicine in the USA is to administer the two drugs within close proximity (24 hours apart) of each other, raising the concern of pharmacokinetic interactions and enhanced anti-inflammatory effects. Objectives: Describe the pharmacokinetics and effects of PBZ on the clearance of FM when administered in close proximity as well as effects on inflammatory mediators. Study design: Two-way randomised balanced crossover experiment. Methods: Twelve Thoroughbred exercised horses received 500 mg FM IV alone or in combination with 2 g of IV PBZ 24 hours later. Blood and urine samples were collected prior to and for up to 120 hours post-drug administration. Whole blood samples were collected at various times and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of FM, PBZ and eicosanoids were measured using LC-MS/MS and noncompartmental pharmacokinetic analysis performed on concentration data. Results: Flunixin meglumine clearance was significantly increased when horses received PBZ 24 hours post-administration (P = .03). No other differences in pharmacokinetic parameters were noted between groups. Thromboxane B 2 was significantly suppressed, relative to baseline for 96 hours post-FM administration. Subsequent administration of PBZ prolonged the suppression. Prostaglandin E2 was decreased for 24 hours following administration of FM with subsequent administration of PBZ prolonging the suppression until 120 hours. PGF 2alpha concentrations were decreased for up to 168 hours post-FM administration. FM administration significantly decreased 15-HETE. Main limitations: Small sample size and lack of a phenylbutazone-only treatment group.

Pharmacokinetics of transdermal flunixin meglumine and effects on biomarkers of inflammation in horses

“…Both conditions are representative of effects on COX‐1. In non‐stimulated serum samples, TXB2 concentrations post‐flunixin meglumine administration were significantly reduced, relative to baseline, starting at 1‐h post‐administration and until 24 h. This is slightly shorter than reports utilizing the same model following intravenous administration, whereby TXB2 concentrations were significantly reduced for up to 96–168 h post‐drug administration (Knych et al, 2020). The difference in the duration of administration is likely attributable to the lower flunixin serum concentrations achieved following transdermal versus intravenous administration.…”

“…In the present reported study, we describe the pharmacokinetics and pharmacodynamics of flunixin meglumine in horses following transdermal administration of an FDA‐approved product for cattle. While administration of transdermal flunixin has not been previously reported in horses, the pharmacokinetics of this compound following intravenous, oral, and intramuscular administration in this species has been well described (Dyke et al, 1997; Knych et al, 2015,2020; Pellegrini‐Masini et al, 2004; Soma et al, 1988).…”

“…Further supporting, the effectiveness of flunixin meglumine as an inhibitor of COX‐2 at the concentrations achieved following transdermal administration was the suppression of PGF2 alpha, observed for up to 48 h post‐administration. It is important to note that inhibition of PGF2 alpha was shorter‐lived following transdermal administration as compared to IV administration (168 h; (Knych et al, 2020)).…”

“…The anti‐inflammatory effects of flunixin meglumine following systemic administration have been well studied using both in vitro (Beretta et al, 2005; Blain et al, 2002; Brideau et al, 2001; Galbraith & McKellar, 1996) and ex vivo (Knych et al, 2020; Lees et al, 1987; Semrad et al, 1985; Soma et al, 1992) models of inflammation. The advantage to using an ex vivo model is that it is directly relevant to the whole animal and considers drug behavior after administration (after it is absorbed and distributed throughout the body).…”

The medication violations in racehorses at Louisiana racetracks from 2016 to 2020

“…Flunixin is recommended for the alleviation of inflammation and pain associated with musculoskeletal disorders in the horse. It is also recommended for the alleviation of visceral pain associated with colic in the horse (Knych et al, 2021;Ziegler et al, 2019). There are many FDA approved formulations of flunixin sold under different trade names reduce muscular spasms (Knych et al, 2016).…”