Libro de Resúmenes del Congreso - Pattern of triclabendazole biotransformation in sheep: identification of the main metabolic pathways.

Congress

Summary *

Benzimidazole (BZD) anthelmintics are extensively metabolized in ruminants. Triclabendazole (TCBZ) is an halogenated BZD compound worldwide used to control immature and adult stages of the liver fluke Fasciola hepatica. Metabolic pathways involved in the hepatic and extra-hepatic biotransformation of different BZD in ruminants have been identified in our laboratory. However, the metabolic pathways involved in the biotransformation of TCBZ remain unknown. The in vitro patterns of hepatic and gastrointestinal (GI) biotransformation of TCBZ and its metabolites in sheep were characterized in the work reported here. Sheep liver microsomes were incubated (30 min) with 40 nmol/mL of either TCBZ and TCBZ-sulphoxide (TCBZSO). Ruminal fluid samples were incubated (10-360 min) under anaerobic conditions with 40 nmol/mL of either TCBZSO and hydroxy-TCBZSO (HO-TCBZSO). Experimental samples were cleaned up an analyzed by HPLC. Liver microsomes biotransformed TCBZ into its sulphoxide, sulphone (TCBZSO2) and hydroxy metabolites. TCBZSO was oxidized to TCBZSO2 and HO-TCBZSO. The oxidation of both substrates was inhibited (P<0.05) after inactivation of the flavin monooxygenase (FMO) system (by heat pre-treatment followed by pre-incubation with methimazole) and in the presence of the cytochrome P450 (CYP) inhibitors piperonyl butoxide and ketoconazole. Thus, both enzymatic pathways are involved in TCBZ (FMO/CYPratio = 74/26) and TCBZSO (51/49) oxidation. The ruminal microflora reduced (sulphoreduction) TCBZSO and HO-TCBZSO into TCBZ and HO-TCBZ, respectively. Understanding of the metabolic fate of TCBZ may be relevant to optimize its flukicidal activity. Overall, the metabolic approach tested here contributes to the identification of the different pathways involved on drug biotransformation in ruminant species. Information provided by the agent in SIGEVA