title: Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep.
abstract: 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), a P-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 B and C received IVM (200mug/kg, subcutaneously) either alone or co-administered with LPM (0.2 mg/kg, twice every 12h), respectively. Individual faecal samples were collected from experimental animals at days -1 and 14 post-treatment to perform the faecal eggs count reduction test (FECRT). Blood samples were collected between 0 and 14 days post-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 (IVM alone) to 96% (IVM+LPM). Haemonchus contortus was highly resistant to IVM. The IVM alone treatment was completely ineffective (0% efficacy) against adult H. contortus. This efficacy value increased up to 72.5% 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 towards improved anthelmintic efficacy was in agreement with the enhanced IVM plasma availability (P<0.05) and prolonged elimination half-life (P<0.05) induced by LPM in infected lambs. A LPM-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.
authors.affiliation: Departamento de Fisiopatología, UNCPBA, Campus Universitario, 7000 Tandil, Argentina. adrianl@vet.unicen.edu.ar
authors.forename: A
authors.initials: A
authors.lastname: Lifschitz
authors.forename: C
authors.initials: C
authors.lastname: Entrocasso
authors.forename: L
authors.initials: L
authors.lastname: Alvarez
authors.forename: M
authors.initials: M
authors.lastname: Lloberas
authors.forename: M
authors.initials: M
authors.lastname: Ballent
authors.forename: G
authors.initials: G
authors.lastname: Manazza
authors.forename: G
authors.initials: G
authors.lastname: Virkel
authors.forename: B
authors.initials: B
authors.lastname: Borda
authors.forename: C
authors.initials: C
authors.lastname: Lanusse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000930:Antidiarrheals / Q000008:administration & dosage; D000977:Antiparasitic Agents / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects*; D005243:Feces / Q000469:parasitology; D007559:Ivermectin / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D008139:Loperamide / Q000008:administration & dosage; D009348:Nematoda / Q000187:drug effects* / Q000502:physiology; D009349:Nematode Infections / Q000188:drug therapy / Q000662:veterinary*; D010270:Parasite Egg Count; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000930:Antidiarrheals; D000977:Antiparasitic Agents; D008139:Loperamide; D007559:Ivermectin