Unchanged triclabendazole kinetics after co-administration with ivermectin and methimazole: failure of its therapeutic activity against triclabendazole-resistant liver flukes

The presence of IVM and MTZ did not affect the plasma disposition kinetics of TCBZ metabolites after the i.r. administration of TCBZ. The AUC value of TCBZ.SO obtained after TCBZ administration (653.9 ± 140.6 μg.h/ml) was similar to that obtained after TCBZ co-administered with IVM and MTZ (650.7 ± 122.8 μg.h/ml). Efficacy values of 56 and 38% were observed for TCBZ alone and for the combined treatment, respectively. No statistical differences (P > 0.05) were observed in fluke counts between treated groups and untreated control, which confirm the resistant status of the Sligo isolate.The presence of IVM and MTZ did not affect the disposition kinetics of TCBZ and its metabolites. Thus, the combined drug treatment did not reverse the poor efficacy of TCBZ against TCBZ-resistant F. hepatica.Triclabendazole (TCBZ, 6-chloro-5(2-3 dichlorophenoxy)-2-methyl thio-benzimidazole), an halogenated benzimidazole (BZD) thiol derivative, shows high efficacy against both the immature and mature stages of Fasciola hepatica in sheep and cattle, which is a differential feature compared to other available trematodicidal drugs [1]. As a consequence of its excellent activity against the liver fluke, it has been extensively used and this has inevitably promoted the selection of TCBZ-resistant populations, which is now a worrying problem in several areas of the world [2,3].Parasites have several possible strategies to achieve drug resistance, including changes in the target molecule, in drug uptake/efflux mechanisms and in drug metabolism [4]. At least two mechanisms appear to be implicated in TCBZ resistance in F. hepatica: increased drug efflux and enhanced oxidative metabolism [5-7]. TCBZ and its sulphoxide metabolite (TCBZ.SO) are both substrates of P-glycoprotein (Pgp) [8]. Over-expression of Pgp has been implicated in the resistance to macrocyclic lactones (ivermectin (IVM), moxidectin (MXD)) [9,10], closantel and BZDs in nematodes [11]), although the exact nature of the role has yet