Bovine liver slices as a model to evaluate metabolic interactions between flukicidal (triclabendazole) and nematodicidal (oxfendazole, fenbendazole) molecules

VIVIANI P.; LIFSCHITZ A.; MATÉ L.; LANUSSE C.; VIRKEL G.

Nantes

Congreso; 13th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2015

13th International Congress of the European Association for Veterinary Pharmacology and Toxicology

IntroductionThe use of anthelmintic combinations in ruminants constitutes a pharmacology-based strategy to manage drug resistance and to expand the spectrum of efficacy of single molecules. In fact, the co-administration of fenbendazole (FBZ) or its main metabolite oxfendazole (OFZ) together with triclabendazole (TCBZ) seems to be advantageous for the concurrent treatment of nematodes and the liver fluke Fasciola hepatica. The aforementioned compounds are cytochrome P450 and flavin-monooxygenase substrates and, consequently, a metabolic interaction upon their co-administration is likely to result. The aim of the present study was to characterise the existence and nature of metabolic interactions occurring in vitro between OFZ/FBZ and TCBZ in liver slices from cattle. Materials and MethodsLiver slices (25.6±3.7 mg wet weight) were produced with a Brendel-Vitron? tissue slicer filled with ice-cold Krebs buffer. Slices were cultured for 12 hours in Williams? Medium E fortified with 50 µM of each anthelmintic (OFZ, FBZ or TCBZ) alone or the combinations OFZ+TCBZ and FBZ+TCBZ. Medium samples were obtained to quantify the accumulation rates (nmol/h) of TCBZ, FBZ, OFZ and their metabolites triclabendazole sulphoxide (TCBZSO) and fenbendazole sulphone (FBZSO2), respectively. In addition, OFZ was further analyzed to quantify the proportion of each of its (-) and (+) stereoisomers.ResultsWhen FBZ was incubated alone, OFZ accumulated in the culture medium at a rate of 0.38±0.20 nmol/h. The accumulation rate increased to 0.73±0.27 nmol/h (p