title: Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.
abstract: Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 μg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States. Electronic address: amarcianae@yahoo.com.
authors.forename: Wesley L
authors.initials: WL
authors.lastname: Shoop
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Hartline
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Brandon R
authors.initials: BR
authors.lastname: Gould
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Waddell
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Richard G
authors.initials: RG
authors.lastname: McDowell
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: Kinney
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: George P
authors.initials: GP
authors.lastname: Lahm
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Long
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Ty
authors.initials: T
authors.lastname: Wagerle
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Gail S
authors.initials: GS
authors.lastname: Jones
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dietrich
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cordova
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schroeder
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Rhoades
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Benner
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Rd., Newark, DE 19714, United States.
authors.forename: Pat N
authors.initials: PN
authors.lastname: Confalone
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018118:Chloride Channels / Q000378:metabolism*; D003058:Cockroaches / Q000187:drug effects; D004283:Dog Diseases / Q000188:drug therapy / Q000503:physiopathology; D004285:Dogs; D004331:Drosophila melanogaster / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D058267:Flea Infestations / Q000188:drug therapy / Q000517:prevention & control / Q000662:veterinary; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009281:Naphthalenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009865:Oocytes / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011897:Random Allocation; D005423:Siphonaptera / Q000187:drug effects*; D013984:Tick Infestations / Q000188:drug therapy / Q000517:prevention & control / Q000662:veterinary; D013987:Ticks / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D000977:Antiparasitic Agents; D018118:Chloride Channels; D007555:Isoxazoles; D009281:Naphthalenes; C000589002:afoxolaner
keywords: Afoxolaner; Dogs; Ectoparasiticide; Fleas; Isoxazoline; Ticks