afoxolaner CAS NO.1093861-60-9

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Definition	Afoxolaner is used to treat and control flea and tick infestations in dogs. After being ingested by a dog, afoxolaner is distributed throughout the dog’s body. When fleas or ticks bite the dog, they are exposed to the drug and killed during their blood meal.
Mechanism of action	Afoxolaner (the active ingredient of NEXGARD) and other isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists, much more selective for GABA receptors in insects or ticks, than for those in mammals, including humans. They bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.This mechanism exists not only in insects but also in mammals and other vertebrates. However the binding affinity of afoxolaner to GABA receptors of invertebrates is much higher than to GABA receptors in vertebrates. For this reason it is significantly less toxic to mammals than to insects and other pests.
Metabolism	Afoxolaner is an isoxazoline compound. It works by blocking the transmissions of neuronal signals in insects. They do this by binding to chloride channels in nerve and muscle cells, causing the receptors to stop working. This in turn paralyses the parasites and kills them.Afoxolaner toxicity to fleas ensures that they die within 24 hours of it being administered. But the dog is unaffected, due to the specific selective nature of the drug.
Pharmacokinetics	Afoxolaner orally administered to dogs was rapidly absorbed into blood. Max. blood levels were reached 2 to 12 hours after administration. Mean half-life in blood ranged from 7.7 to 17.8 days. Bioavailability was estimated to be approx. 74%. Half-life was higher in Collies than in Beagles, but no serious adverse effects were observed after treatment of Collies at 25 mg/kg bw (i.e. ~10x the therapeutic dose).Absorbed afoxolaner binds strongly (>99%) to blood proteins but it seems not to cause displacement of other drugs with high protein binding capacities.In dogs afoxolaner is slowly broken down into various metabolites, the major ones being a hydroxylate and a glucuronide. Elimination of both the metabolites and the parent compound occurrs mainly via biliary excretion and to a lesser extent through urine.

 

 

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