title: Endectocide exchanges between grazing cattle after pour-on administration of doramectin, ivermectin and moxidectin.
abstract: Self-licking behaviour in cattle has recently been identified as a determinant of the kinetic disposition of topically-administered ivermectin. In the present study, we document the occurrence and extent of transfer between cattle of three topically-administered endectocides, as a consequence of allo-licking. Four groups of two Holstein cows each received one pour-on formulation of doramectin, ivermectin, or moxidectin, or no treatment. The cows were then kept together in a paddock. Systemic exposure to each topically-administered endectocide was observed in at least five of six non-treated cattle. Plasma and faecal drug concentration profiles in non-treated animals were highly variable between animals and within an animal, and sometimes attained those observed in treated animals. Drug exchanges were quantified by measuring plasma and faecal clearances after simultaneous i.v. administration of the three drugs as a cocktail. Plasma clearances were 185+/-43, 347+/-77 and 636+/-130ml/kg/day, faecal clearances representing 75+/-26, 28+/-13, and 39+/-30% of the plasma clearance for doramectin, ivermectin and moxidectin, respectively. The amount of drug ingested by non-treated cattle attained 1.3-21.3% (doramectin), 1.3-16.1% (ivermectin), 2.4-10.6% (moxidectin) of a pour-on dose (500 microg/kg). The total amount of drug ingested by all non-treated cattle represented 29% (doramectin), 19% (ivermectin), and 8.6% (moxidectin) of the total amount of each drug poured on the backs of treated animals. The cumulative amounts of endectocide ingested by each non-treated cow ranged from 1.3 to 27.4% of a pour-on dose. Oral bioavailability after drug ingestion due to allo-licking was 13.5+/-9.4, 17.5+/-3.5 and 26.1+/-11.1% for doramectin, ivermectin and moxidectin, respectively. The extent of drug exchange demonstrated here raises concerns for drug efficacy and safety, emergence of drug resistance, presence of unexpectedly high residue levels in treated and/or untreated animals and high environmental burdens. Moreover, scientific and regulatory aspects of clinical and bioequivalence trials for topical drug administration in cattle should be explored.
authors.affiliation: UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, B.P. 87614, 31076 Toulouse cedex 03, France. a.bousquet-melou@envt.fr
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Mélou
authors.forename: Sonia
authors.initials: S
authors.lastname: Mercadier
authors.forename: Michel
authors.initials: M
authors.lastname: Alvinerie
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D001522:Behavior, Animal; D001682:Biological Availability; D002417:Cattle / Q000097:blood / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D007306:Insecticides / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D007559:Ivermectin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D018942:Macrolides / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics
chemical_list: D004338:Drug Combinations; D007306:Insecticides; D018942:Macrolides; D007559:Ivermectin; C084101:doramectin; C027837:moxidectin