Oral and intravenous administration of nimesulide in the horse: rational dosage regimen from pharmacokinetic and pharmacodynamic data.
BACKGROUND
The selective COX-2-inhibitor nimesulide is used extra-label in equine veterinary practice as an anti-inflammatory agent. However, there are no data on which to base the rational use of the drug in this species.


OBJECTIVE
To determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule.


METHODS
The pharmacokinetics of nimesulide in the horse after oral administration (1 mg/kg bwt), and oral and i.v. administration (1.5 mg/kg bwt) were investigated, effects of feeding status on bioavailability determined, and plasma protein binding of the drug and its principal metabolites measured. Compartmental and noncompartmental pharmacokinetic analyses were performed. The plasma concentration-time profile was used, together with in vitro literature data on nimesulide inhibition of COX isoforms, to determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule.


CONCLUSIONS
The findings suggest that 1.5 mg/kg bwt may produce adequate clinical effects, and the dosing interval should be 12-24 h depending on condition severity. However, at that dose, the concentration in the animal exceeds the in vitro IC50 for both isoforms, so that COX-1/COX-2 selectivity is lost and side-effects due to COX-1 inhibition are a possibility. Nimesulide should therefore be used with caution in equine clinical practice.
Villa
R
R
Department of Veterinary Sciences and Technologies for Food Safety, University of Milan, Via Celoria, 10, 20133 Milan, Italy.
Cagnardi
P
P
Belloli
C
C
Zonca
A
A
Zizzadoro
C
C
Ferro
E
E
Carli
S
S
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006734:Horse Diseases / Q000188:drug therapy*; D006736:Horses; D007275:Injections, Intravenous / Q000662:veterinary; D008297:Male; D011897:Random Allocation; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; C012655:nimesulide