Relative activity of triclabendazole metabolites against the liver fluke, Fasciola hepatica.
A study has been carried out to determine the relative activity of triclabendazole (TCBZ) and its sulphoxide (TCBZSO) and sulphone (TCBZSO(2)) metabolites against the adult stage of the liver fluke, Fasciola hepatica. Flukes were incubated for 24h in vitro in 15mug/ml of each of the compounds and prepared for scanning and transmission electron microscopy. All three compounds induced changes to the surface morphology of the fluke, the changes comprising swelling and blebbing to a greater or lesser extent in different regions of the fluke. TCBZSO(2) was more disruptive anteriorly and TCBZSO posteriorly. Internal ultrastructural changes were evident following incubation with each of the compounds, with an order of severity TCBZSO(2)>TCBZSO>TCBZ. Swelling of the basal infolds and mitochondria were observed in the tegumental syncytium. In the tegumental cell bodies, there was a reduction in the number of secretory bodies, disruption of the Golgi complexes and swelling of the mitochondria. Severe flooding of the internal tissues was observed with TCBZSO(2) and, to a lesser extent, with TCBZSO and TCBZ. The results demonstrate that both TCBZ and TCBZSO(2) are capable of disrupting the fluke in vitro and are not the inactive compounds they were assumed to be previously. They may well contribute to drug action in vivo as well, indicating that drug action is due to the additive effects of several metabolites, rather than being due to a single active metabolite, namely, TCBZSO.
Halferty
L
L
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, The Queen's University of Belfast, Belfast BT9 7BL, United Kingdom.
Brennan
G P
GP
Trudgett
A
A
Hoey
L
L
Fairweather
I
I
D000818:Animals; D000871:Anthelmintics / Q000378:metabolism* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism* / Q000494:pharmacology*; D005210:Fasciola hepatica / Q000187:drug effects* / Q000648:ultrastructure; D013454:Sulfoxides / Q000494:pharmacology*; D000077682:Triclabendazole
D000871:Anthelmintics; D001562:Benzimidazoles; D013454:Sulfoxides; D000077682:Triclabendazole; C085104:triclabendazole sulfoxide