title: Intravascular plasma disposition and salivary secretion of closantel and rafoxanide in sheep.
abstract: The plasma and salivary disposition of closantel and rafoxanide were examined following intravenous administration in adult sheep. Two studies were conducted 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 best described by a 2-compartmental model with 1st-order rate constants. Plasma disposition of closantel and rafoxanide were characterised by a rapid distribution (t1/2(alpha)) of <30 min), long elimination half-life (t1/2(beta)) of 17.0 +/- 4.0 days for closantel and 7.2 +/- 0.6 days for rafoxanide), small apparent volume of distribution (V(SS) of <0.15 l/kg) and a slow rate 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 as 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 differences were observed in the rate measurements of distribution (k12, k21 and t1/2(alpha)), whereas the parameters of elimination (k10, t1/2(beta) and Cl), were more consistent between animals. A dose proportional increase 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 microg/mL) and rafoxanide (mean of 0.07 +/- 0.04 microg/mL) was observed during the 24-h examination period after dosing.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa.
authors.forename: G E
authors.initials: GE
authors.lastname: Swan
authors.forename: H A
authors.initials: HA
authors.lastname: Koeleman
authors.forename: H S
authors.initials: HS
authors.lastname: Steyn
authors.forename: M S
authors.initials: MS
authors.lastname: Mülders
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007275:Injections, Intravenous / Q000662:veterinary; D008297:Male; D010865:Pilot Projects; D011888:Rafoxanide / Q000097:blood / Q000493:pharmacokinetics*; D012458:Salicylanilides / Q000097:blood / Q000493:pharmacokinetics*; D012463:Saliva / Q000378:metabolism*; D012756:Sheep / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet / Q000662:veterinary; D013997:Time Factors
chemical_list: D000871:Anthelmintics; D012458:Salicylanilides; D011888:Rafoxanide; C023342:closantel