Intravascular plasma disposition and salivary secretion of closantel and rafoxanide in sheep

The plasma and salivary disposition of closantel and rafoxanide were examin ed following intravenous administration in adult sheep. Two studies were co nducted with rafoxanide at 7.5 mg/kg and 1 with closantel using 2 doses (5 and 15 mg/kg). The pharmacokinetic profile of both drugs in plasma were bes t described by a 2-compartmental model with Ist-order rate constants. Plasm a disposition of closantel and rafoxanide were characterised by a rapid dis tribution (t1/2((alpha)) of < 30 min), long elimination half-life (t1/2((be ta)) of 17.0 +/- 4.0 days for closantel and 7.2 i 0.6 days for rafoxanide), small apparent volume of distribution (V-SS of < 0.15 l/kg) and a slow rat e of total body clearance (Cl of <0.01 ml/min/kg). The area under the drug plasma concentration curve (AUC) of closantel at 5 mg/kg was nearly twice a s large as that of rafoxanide at 7.5 mg/kg resulting from the slower t1/2(( beta)) observed with closantel compared to rafoxanide. Large individual dif ferences were observed in the rate measurements of distribution (k(12) k(21 ) and t1/ 2((alpha))), whereas the parameters of elimination (k(10) t1/2((b eta)) and CI), were more consistent between animals. A dose proportional in crease in AUC was observed for closantel administered at 5 and 15 mg/kg. A low, constant salivary concentration of closantel (mean of 0.04 +/- 0.05 mu g/ml) and rafoxanide (mean of 0.07 +/- 0.04 mu g/ml) was observed during t he 24-h examination period after dosing.