title: Triclabendazole sulfoxide causes stage-dependent embryolethality in zebrafish and mouse in vitro.
abstract: BACKGROUND
  Fascioliasis and paragonimiasis are widespread foodborne trematode diseases, affecting millions of people in more than 75 countries. The treatment of choice for these parasitic diseases is based on triclabendazole, a benzimidazole derivative which has been suggested as a promising drug to treat pregnant women and children. However, at the moment, this drug is not approved for human use in most countries. Its potential adverse effects on embryonic development have been scarcely studied, and it has not been assigned a pregnancy category by the FDA. Thus, to help in the process of risk-benefit decision making upon triclabendazole treatment during pregnancy, a better characterization of its risks during gestation is needed.
  
  
  METHODS
  The zebrafish embryo test, a preimplantation and a postimplantation rodent whole embryo culture were used to investigate the potential embryotoxicity/teratogenicity of triclabendazole and its first metabolite triclabendazole sulfoxide. Albendazole and albendazole sulfoxide were included as positive controls.
  
  
  RESULTS
  Triclabendazole was between 10 and 250 times less potent than albendazole in inducing dysmorphogenic effects in zebrafish or postimplantation rodent embryos, respectively. However, during the preimplantation period, both compounds, triclabendazole and triclabendazole sulfoxide, induced a dose-dependent embryolethal effect after only 24 h of exposure in rodent embryos and zebrafish (lowest observed adverse effect concentrations = 10 μM).
  
  
  CONCLUSIONS
  In humans, after ingestion of the recommended doses of triclabendazole to treat fascioliasis and paragonimiasis (10 mg/kg), the main compound found in plasma is triclabendazole sulfoxide (maximum concentration 38.6 μM), while triclabendazole concentrations are approximately 30 times lower (1.16 μM). From our results it can be concluded that triclabendazole, at concentrations of the same order of magnitude as the clinically relevant ones, does not entail teratogenic potential in vitro during the organogenesis period, but its first metabolite triclabendazole sulfoxide has a high embryotoxic capacity in vitro during the preimplantation stage.
authors: GRET-CERETOX, INSA-UB and Toxicology Unit, Pharmacology and Therapeutical Chemistry Department, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors: Nuria
authors: N
authors: Boix
authors: GRET-CERETOX, INSA-UB and Toxicology Unit, Pharmacology and Therapeutical Chemistry Department, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Elisabet
authors: E
authors: Teixido
authors: Departament de Biologia Cellular, Fisiologia i Immunologia, Unitat de Biologia Cellular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Marta
authors: M
authors: Vila-Cejudo
authors: Facultad de Ciencias Veterinarias, Universidad Nacional de Cajamarca, Cajamarca, Perú
authors: Pedro
authors: P
authors: Ortiz
authors: Departament de Biologia Cellular, Fisiologia i Immunologia, Unitat de Biologia Cellular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Elena
authors: E
authors: Ibáñez
authors: GRET-CERETOX, INSA-UB and Toxicology Unit, Pharmacology and Therapeutical Chemistry Department, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors: Juan M
authors: JM
authors: Llobet
authors: GRET-CERETOX, INSA-UB and Toxicology Unit, Pharmacology and Therapeutical Chemistry Department, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors: Marta
authors: M
authors: Barenys
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D046149:Embryo Culture Techniques; D010064:Embryo Implantation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects*; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D017207:Rats, Sprague-Dawley; D013454:Sulfoxides / Q000494:pharmacology*; D000077682:Triclabendazole; D015027:Zebrafish / Q000196:embryology*
chemical_list: D001562:Benzimidazoles; D013454:Sulfoxides; D000077682:Triclabendazole; C085104:triclabendazole sulfoxide