Preclinical evaluation of phenosanic acid safety and toxicokinetics

Detailed post-marketing studies of phenosanoic acid, the active ingredient of the original domestic medicinal product Dibufelon®, approved for human medical use as an antiepileptic agent, are aimed at improving its clinical use.

Objective - analysis of toxic properties, immunotoxicity, toxicokinetics and elements of drug dependence development, assessment of possible carcinogenic properties of phenosanoic acid in sexually mature beagle dogs with repeated oral administration with a period of delayed observation.

Materials and methods. Phenosanoic acid was administered orally to dogs (control group of animals, 2 males and 2 females and 3 experimental groups of animals of 5 males and 5 females) for 270 days at doses of 24, 60 and 120 mg/kg (1; 2.5 and 5 higher therapeutic doses (VTD), respectively). The general toxic properties, local irritating effect, effect on immunocompetent organs, elements of drug dependence development, possible carcinogenic properties, as well as basic pharmacococcinetic parameters (C_max, T_max, AUC_0-24, MRT, T_1/2) were evaluated.

Results. the drug phenosanoic acid did not have a locally irritating, immunotoxic and carcinogenic effect, did not cause withdrawal syndrome. Neurological and behavioral abnormalities (tremors, isolated cases of slight depression of behavior and refusal of feed) were detected when the drug was administered mainly at medium and maximum doses. No dose of no apparent adverse effect (NOAEL) was established (less than 24 mg/kg). Toxicokinetic analysis showed no cumulation of the active ingredient after repeated oral administration.

Conclusion. the use of phenosanoic acid should take into account possible side effects (neurological and behavioral) that are associated with the direct pharmacological profile of the drug. Keywords: phenosanic acid; safety; toxicokinetics; preclinical studies.

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