METABOLIC INTERFERENCE ENHANCES THE PLASMA PROFILES OF TRICLABENDAZOLE METABOLITES IN SHEEP.

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

Gent, Belgica

Congreso; WAAVP 2007; 2007

WAAVP

TCBZ is metabolised by both flavin-monooxygenase (FMO) and cytochrome P450 (CYP) enzymatic systems in the liver. Interfering with these metabolic pathways may be useful to improve the availabilities of TCBZ and its metabolites, which may have impact on their efficacy against Fasciola hepatica. The plasma pharmacokinetic behaviour of TCBZ metabolites was evaluated following TCBZ co-administration with known FMO [methimazole (MTZ)] and CYP inhibitors [piperonyl butoxyde (PB) and ketoconazole (KTZ)] in sheep. Twenty (20) healthy Corriedale sheep (18 kg) were randomly allocated into 4 groups and treated with: a) TCBZ alone (5 mg/kg IV, control group); 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 metabolites were detected in plasma after all TCBZ treatments. Compared to control values, TCBZ sulphoxide plasma Cmax increased after TCBZ+PB (61.6 %, P<0.01) and TCBZ+KTZ (36.9 %, P<0.05) treatments. TCBZ sulphoxide plasma availability (measured as AUC) was also greater when TCBZ was co-administered with both metabolic inhibitors (TCBZ+PB=99.1 %, P<0.01; TCBZ+KTZ=40.7 %, P<0.05). MTZ did not modified the pharmacokinetic behaviour of TCBZ sulphoxide under this experimental conditions. CYP-mediated inhibition of TCBZ oxidation in the liver accounted for the increased plasma 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.