Characterization of intramuscular Isoflupredone acetate in horses: pharmacokinetics and effects on anti-inflammatory mediators and plasma electrolytes.

Abstract

BACKGROUND: Corticosteroids, such as isoflupredone, are effective anti-inflammatory medications and as such are commonly used to treat inflammation associated with training and injuries in performance horses. While the pharmacokinetics and pharmacodynamics of isoflupredone acetate (IPA) following intra-articular administration to horses has been well described, studies characterizing intramuscular (IM) administration are lacking. The objective of the current study was to describe the pharmacokinetics and anti-inflammatory effects of IPA following IM administration to horses. Twelve horses received a single IM dose of 20 mg IPA, and blood and urine samples were collected starting at 5 min (blood) and 24 h (urine) until 312 h. Concentrations of isoflupredone were determined using liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis performed. The pharmacodynamic effects of the drug were assessed by measuring endogenous cortisol concentrations and effects on concentrations of inflammatory biomarkers utilizing an ex vivo model of inflammation. RESULTS: The C, T, and terminal half-life of isoflupredone were 1.55 ± 0.43 ng/mL, 3.50 h (0.16-5.0 h; median and range), and 39.6 ± 22.1 h, respectively. For compartmental modeling, a 1-cmpt model best fit the data. Based on Monte Carlo simulations, for a simulated population of 1000 horses, a detection time of 10 days is recommended for isoflupredone concentrations in 99% of the population to fall below the currently recommended 100 pg/mL regulatory screening limit. Isoflupredone urine concentrations were below the limit of quantitation (0.05 ng/mL) in all horses by 360 h. Significant suppression of endogenous cortisol was observed for 312 h. Stimulation of isoflupredone treated blood with lipopolysaccharide and calcium ionophore resulted in increasing concentrations of several inflammatory biomarkers produced by cyclooxygenase and 15-lipooxygenase, suggesting that the isoflupredone blood concentrations following intramuscular administration may not have been adequate to suppress the activity of these enzymes. A significant decrease in concentration of leukotriene B4 and 5-HETE suggest suppression of 5-lipooxygenase activity by isoflupredone. A single IM administration of IPA resulted in hypokalemia and a significant increase in urinary fractional excretion of potassium. CONCLUSION: The prolonged detection time and pharmacologic effects of isoflupredone acetate warrant an extended withdrawal time for IM administration prior to competition in performance horses.