Resistance induced changes on TCBZ-transport in Fasciola hepatica: ivermectin reversal effect

MOTTIER, L.; ALVAREZ, L.; FAIRWEATHER, I; LANUSSE, C.

JOURNAL OF PARASITOLOGY

AMER SOC PARASITOLOGISTS

Año: 2006 vol. 92 p. 1355 - 1360

0022-3395

  Triclabendazole (TCBZ) and albendazole (ABZ) are flukicidal benzimidazole compounds extensively used in veterinary medicine. While TCBZ has excellent activity against mature and immature stages of the liver fluke Fasciola hepatica, ABZ action is restricted to flukes older than 12 weeks. The intensive use of TCBZ has resulted in the development of resistance. To gain some insight into the mechanisms of resistance to TCBZ, the ex vivo diffusion of TCBZ, TCBZ sulphoxide (TCBZSO, the active metabolite of TCBZ) and ABZ into TCBZ-susceptible and -resistant adult flukes was compared. TCBZ-susceptible (Cullompton) and –resistant (Sligo) flukes were incubated in Krebs Ringer Tris buffer with either TCBZ, TCBZSO or ABZ (5 nmol/ml) for 90 min. Drug/metabolites concentrations were quantified by HPLC. All the assayed molecules penetrated through the tegument of both susceptible and resistant flukes. However, significantly lower concentrations of TCBZ and TCBZSO were recovered within the TCBZ-resistant flukes. In contrast, ABZ entrance into the susceptible and resistant flukes was equivalent. The influx/efflux balance for TCBZ, TCBZSO and ABZ in susceptible and resistant flukes in the presence/absence of a substrate (ivermectin) of the drug transporter P-glycoprotein was assessed. The ivermectin-induced modulation of P-glycoprotein activity decreased TCBZ efflux from the resistant flukes. Higher concentrations of TCBZ and TCBZO were recovered from the resistant liver flukes in the presence of ivermectin. Thus, an altered influx/efflux mechanism may account for the development of resistance to TCBZ in F. hepatica.