In vivo preliminary investigations of the effects of the benzimidazole anthelmintic drug flubendazole on rat embryos and fetuses

•Flubendazole-ASD is highly bioavailable and it is active as macrofilaricide.•Embryotoxicity of flubendazole-ASD is evaluated after oral maternal treatment on GD 9.5 and 10.5.•Flubendazole-ASD is embryolethal at 6.32mg/kg/day (Cmax=0.801μg/mL).•Flubendazole-ASD is teratogenic at 3.46mg/kg/day (Cmax=...

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Published in:Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2014-11, Vol.49, p.33-42
Main Authors: Longo, Monica, Zanoncelli, Sara, Messina, Monica, Scandale, Ivan, Mackenzie, Charles, Geary, Timothy, Marsh, Kennan, Lindley, David, Mazué, Guy
Format: Article
Language:English
Subjects:
Animals
Anthelmintics - blood
Anthelmintics - toxicity
Benzimidazole anthelmintic
Dose-Response Relationship, Drug
Embryo, Mammalian - drug effects
Embryolethality
Embryonic Development - drug effects
Eye development
Female
Fetus - drug effects
Filarial diseases
Flubendazole
Mebendazole - analogs & derivatives
Mebendazole - blood
Mebendazole - toxicity
Pregnancy
Rats
Rats, Sprague-Dawley
Teratogenicity
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Summary:•Flubendazole-ASD is highly bioavailable and it is active as macrofilaricide.•Embryotoxicity of flubendazole-ASD is evaluated after oral maternal treatment on GD 9.5 and 10.5.•Flubendazole-ASD is embryolethal at 6.32mg/kg/day (Cmax=0.801μg/mL).•Flubendazole-ASD is teratogenic at 3.46mg/kg/day (Cmax=0.539μg/mL). Flubendazole, in a new formulation with high systemic bioavailability, has been proposed as a macrofilaricide against filarial diseases. To investigate embryotoxic activity, the new flubendazole formulation was administered orally to Sprague Dawley rats at 2, 3.46, 6.32mg/kg/day on gestation day (GD) 9.5 and 10.5. Embryos/fetuses were evaluated on GD 11.5, 12.5 or 20. At 6.32mg/kg/day (Cmax=0.801μg/mL after single administration), flubendazole initially induced an arrest of embryonic development followed by a generalized cell death that led to 100% embryolethality by GD 12.5. At 3.46mg/kg/day (Cmax=0.539μg/mL after single administration), flubendazole markedly reduced embryonic development by GD 12.5 without causing cell death. On GD 20, 80% of fetuses showed malformations. At 2mg/kg/day (Cmax=0.389μg/mL after single administration), it did not interfere with rat embryofetal development.
ISSN:0890-6238
1873-1708
DOI:10.1016/j.reprotox.2014.06.009