Metabolic interference enhances the plasma profiles of triclabendazole metabolites in sheep.

VIRKEL, G.; LIFSCHITZ, A.; BALLENT, M.; SALLOVITZ, J.; SCARCELLA, S.; LANUSSE, C.

Ghent, Bélgica

Congreso; 21th. International Conference of the World Association for the Advancement of Veterinary Parasitology; 2007

World Association for the Advancement of Veterinary Parasitology

Understanding triclabendazole (TCBZ) kinetic and metabolism patterns is critical to optimise its flukicidal activity. TCBZ is metabolised by both flavin-monooxygenase (FMO) and cytochrome P450 (CYP) enzymatic systems in the liver. Interference with these metabolic pathways may be useful to increase the systemic availabilities of TCBZ and its metabolites, which may improve the efficacy against Fasciola hepatica. The plasma disposition of TCBZ metabolites was evaluated following TCBZ co-administration with FMO [methimazole (MTZ)] and CYP [piperonyl butoxyde (PB) and ketoconazole (KTZ)] inhibitors in sheep. Twenty (20) healthy female Corriedale sheep were randomly allocated into 4 treated groups:  a) TCBZ alone (5 mg/kg, IV,); b) TCBZ (5 mg/kg, IV) + MTZ (3 mg/kg, IV); c) TCBZ (5 mg/kg, IV) + PB (30 mg/kg, IV) and d) TCBZ (5 mg/kg, IV) + KTZ (10 mg/kg, Oral). Blood samples were taken over 240 h post-treatment and analysed by HPLC. TCBZ sulphoxide and sulphone were the main metabolites recovered in plasma after all treatments. MTZ did not affect the pharmacokinetics of TCBZ. TCBZ sulphoxide peak concentrations significantly increased after the TCBZ+PB (62 %) and TCBZ+KTZ (40 %) treatments compared to those measured in the TCBZ alone treatment. TCBZ sulphoxide plasma availability (measured as AUC) was also higher in the presence of both PB (99%) and KTZ (41%) metabolic inhibitors. CYP-mediated inhibition of TCBZ oxidation in the liver accounted for the increased systemic availability of its active metabolite TCBZ sulphoxide. These results should be considered among other strategies to improve the use of this trematodicidal drug in ruminants.