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 dis- eases 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 em- bryonic development have been scarcely studied, and it has not been assigned a pregnan- cy 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 ges- tation is needed. Methodology The zebrafish embryo test, a preimplantation and a postimplantation rodent whole embryo culture were used to investigate the potential embryotoxicity/teratogenicity of triclabenda- zole and its first metabolite triclabendazole sulfoxide. Albendazole and albendazole sulfox- ide were included as positive controls. Principal Findings 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 tricla- bendazole sulfoxide, induced a dose-dependent embryolethal effect after only 24 h ofexposure in rodent embryos and zebrafish (lowest observed adverse effect concentra- tions = 10 μ M). Conclusions/Significance 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 sulf- oxide (maximum concentration 38.6 μ M), while triclabendazole concentrations are approxi- mately 30 times lower (1.16 μ M). 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