Orally administered torsemide in horses: pharmacokinetic and pharmacodynamic studies

Abstract

Diuretic therapy is the mainstay for management of congestive heart failure in horses. Loop-diuretic medications in horses have been restricted to injectable medications because currently, no data support the use of orally-administered loop diuretics. The objectives of this study were to determine the pharmacokinetic and pharmacodynamic properties of the orally-administered, loop-diuretic torsemide and determine if it could be used as an alternative to injectable diuretics in the horse. A total of 6 healthy adult mares were used in a 2-phase, prospective study. The two phases consisted of the pharmacokinetic profiling of a single dose (6 mg/kg PO) and pharmacodynamic effects of long-term torsemide administration (2 mg/kg q12h) for 6 days in healthy horses. Pharmacokinetic analysis identified a peak concentration (Cmax) of 10.14 µg/mL (range, 6.793-14.69 µg/mL) and elimination half-life (T1/2) 9.205 hours (range, 8.383-10.43 hours). The area under the plasma drug concentration over time curve (AUC) was 80.7 µg ˟ h/mL (range, 56.5-117.2 µg ˟ h/mL). A statistically significant increase in urine volume and decrease in urine specific gravity were found between day 0 (baseline) and day 6 (p<0.0001). Significant alterations in biochemical variables included hyponatremia, hypokalemia, hypochloremia, and increased serum creatinine concentration. Mean arterial blood pressure significantly decreased on day 6 (57.67±8.814 mmHg, p=0.001) as compared to baseline (78±6.132 mmHg). Serum aldosterone concentrations significantly increased after 6 days of torsemide administration (p=0.0006). Orally-administered torsemide (4 mg/kg/day) successfully reached therapeutic concentrations in blood, induced clinically relevant diuresis, and resulted in moderate pre-renal azotemia and electrolyte disturbances.