Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep.

LIFSCHITZ, A; ENTROCASSO C,; ALVAREZ L; LLOBERAS, M; BALLENT M; MANAZZA J; VIRKEL, G; LANUSSE C

VETERINARY PARASITOLOGY

ELSEVIER SCIENCE BV

Año: 2010 vol. 172 p. 291 - 298

0304-4017

The in vivo co-administration of ivermectin(IVM)with P-glycoprotein(P-gp)modulator agents has been shown to enhance its systemic availability. However, there is no sufficient evidence on the impact that this type of drug–drug interaction may have on the in vivo efficacy against resistant nematodes in ruminant species. The current work reports on the effects of loperamide(LPM),aP-gp modulating agent,on both IVM kinetic behaviour and anthelmintic activity in infected lambs.Eighteen(18)lambs naturally infected with IVM-resistant gastrointestinal nematodes were allocated into three(3)experimental groups. Group A remained as untreated control. Animals in Groups Band Creceived IVM(200g/kg, subcutaneously) either alone or co-administered with LPM(0.2mg/kg,twiceevery12h), respectively. Individual faecal samples were collected from experimental animals at days −1 and14post-treat ment to perform the faecal eggs countreduction test(FECRT).Blood samples were collected between 0 and 14 dayspost-treatment and IVM plasma concentrations were determined by HPLC. Additionally,at day 14 post-treatment,lambs from all experimental groups were sacrificed and adult gastrointestinal nematode counts were performed. FECRT values increased from 78.6(IVMalone)to96%(IVM+LPM). Haemonchus contortus was highly resistant to IVM. The IVM alone treat ment was completely ineffective (0%efficacy)again stadult H. contortus. This efficacy value increased up to72.5% in the presence of LPM. The efficacy against Trichostrongylus colubriformis increased from 77.9% (IVM alone)to 96.3%(IVM+LPM).The described favorable tendency toward simproved anthelmintic efficacy was in agreement with the enhanced IVM plasma availability(P < 0.05) and prolongede limination half-life(P < 0.05)induced by LPM in infected lambs.ALPM- induced P-gp modulation increases IVM systemic exposure in the host but also it may reduce P-gp efflux transport over-expressed in target resistant nematodes.