The metabolism and fate of closantel (Flukiver) in sheep and cattle.
Closantel was reasonably well absorbed in sheep and cattle. After oral (10 mg/kg) or parenteral (5 mg/kg) administration, similar peak times (8-48 h) and peak plasma levels (45-55 micrograms/mL) are observed. Plasma level-time curves are superimposable for either route and increase linearly with the dose. The elimination half-life of closantel is 2 to 3 weeks. The relative bioavailability of 50% of oral closantel can partly be explained by incomplete absorption. Experiments in sheep with 14C-closantel revealed that the plasma radioactivity is almost exclusively due to the unmetabolized drug, metabolites accounting for less than 2%. At least 80% of the dose was excreted with the feces over the investigational period of 8 weeks, and less than 0.5% with the urine. Closantel was only poorly metabolized. Over 90% of the fecal radioactivity was due to the parent compound. Two monoiodoclosantel isomers were the only fecal metabolites detected with radio-HPLC. The distribution of closantel to tissues was limited by its high protein binding. Closantel bound strongly (greater than 99.9%) and almost exclusively to plasma albumin. Accordingly, tissue concentrations were many times lower than the corresponding plasma levels. Residual radioactivity in sheep in all tissues but liver was entirely due to closantel. About 30% to 40% of the liver radioactivity could be attributed to monoiodoclosantel. In both sheep and cattle, residual tissue concentrations decline parallel to the plasma concentrations. Consequently, the plasma kinetics of closantel reliably reflect its depletion from tissues. Independently of the dosing scheme and route of administration, the maximum daily intake by the consumer was always below the acceptable daily intake within 4 weeks after the last dose.
Michiels
M
M
Department of Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutica, Beerse, Belgium.
Meuldermans
W
W
Heykants
J
J
D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004350:Drug Residues / Q000032:analysis; D005260:Female; D008297:Male; D012457:Salicylamides / Q000378:metabolism*; D012458:Salicylanilides / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D012756:Sheep; D014018:Tissue Distribution
D000871:Anthelmintics; D012457:Salicylamides; D012458:Salicylanilides; C023342:closantel