Abstract
Isoxazoline derivatives have rapidly become cornerstone ectoparasiticides in veterinary medicine, providing high efficacy and long-lasting protection against fleas, ticks, and other arthropods in companion animals and, more recently, in food-producing species. This review summarizes current knowledge on the chemistry, pharmacology, and toxicology of the main veterinary isoxazolines - fluralaner, afoxolaner, sarolaner, and lotilaner - with particular emphasis on safety profiles and broader One Health considerations. Chemically, these compounds are highly lipophilic, fluorinated molecules with distinctive stereochemistry; the selective use of biologically active S-enantiomers has improved potency while limiting off-target effects. Isoxazolines act through non-competitive antagonism of γ-aminobutyric acid (GABA) - and L-glutamate-gated chloride channels in arthropods, resulting in sustained neuronal hyperexcitation and parasite death, with markedly higher affinity for arthropod than mammalian receptors. Pharmacokinetically, the compounds exhibit variable oral bioavailability but share extensive plasma protein binding, large volumes of distribution, low clearance, and long elimination half-lives, which underlie their prolonged clinical efficacy but also raise concerns regarding tissue accumulation and delayed adverse effects. Controlled studies generally demonstrate wide safety margins; however, post-marketing pharmacovigilance has identified rare but sometimes serious neurological adverse events, particularly in predisposed animals or in the context of impaired efflux transport, such as ABCB1/MDR1 mutations or P-glycoprotein inhibition. The authorization of fluralaner for use in laying hens and evidence of residues in eggs approaching established maximum residue limits emphasize the importance of continued residue monitoring and refinement of withdrawal periods. Moreover, the environmental persistence of isoxazolines and their pronounced toxicity to non-target invertebrates highlight emerging ecotoxicological concerns. Collectively, veterinary isoxazolines represent a highly effective yet complex class of antiparasitic agents whose safe and sustainable use requires integrated pharmacological, toxicological, residue, and environmental risk assessment.