title: Influence of Pluronic 85 and ketoconazole on disposition and efficacy of ivermectin in sheep infected with a multiple resistant Haemonchus contortus isolate.
abstract: Non-specific mechanisms involving ATP-binding cassette drug efflux transporters may play an important role in xenobiotic clearance in ovine gastro-intestinal nematodes. By using transporter inhibitors, the aim of this trial was to assess the possibility of increasing drug bioavailability in the host in an attempt to improve treatment efficacy. Thirty-six lambs were infected with 5000 multiple-drug resistant Haemonchus contortus third stage larvae and separated into six groups (n=6): ivermectin alone (IVM; 0.2 mg/kg body-weight, BW), ketoconazole alone (KET; 10 mg/kg BW), Pluronic 85 alone (P85; 4 mg/kg BW), IVM+KET, IVM+P85 or untreated control. Ivermectin was administered once on day 28 post-infection for all appropriate groups, whereas KET and P85 were administered as five separate doses on day 26-30 post-infection inclusive. The resultant data showed that concomitant administration of KET or P85 with IVM induced increases in plasma and tissue concentrations of IVM in treated animals, resulting in a two-fold increase in the area under the time-concentration curve (p<0.05). Faecal egg counts and worm burdens of the IVM+KET and IVM+P85 groups were lower than in the untreated, KET and P85 alone control animals. Worm burdens were reduced by between 16% and 51% with IVM+KET and IVM+P85 respectively compared to untreated control animals. The co-administration of P85 with IVM increased the efficacy by 34%, compared with IVM alone, in terms of worm count reduction of the multi-resistant isolate of H. contortus.
authors.affiliation: Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, EH26 0PZ, UK. dave.bartley@moredun.ac.uk
authors.forename: D J
authors.initials: DJ
authors.lastname: Bartley
authors.forename: A A
authors.initials: AA
authors.lastname: Morrison
authors.forename: J
authors.initials: J
authors.lastname: Dupuy
authors.forename: Y
authors.initials: Y
authors.lastname: Bartley
authors.forename: J F
authors.initials: JF
authors.lastname: Sutra
authors.forename: C
authors.initials: C
authors.lastname: Menez
authors.forename: M
authors.initials: M
authors.lastname: Alvinerie
authors.forename: F
authors.initials: F
authors.lastname: Jackson
authors.forename: L
authors.initials: L
authors.lastname: Devin
authors.forename: A
authors.initials: A
authors.lastname: Lespine
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000018:Abomasum; D000818:Animals; D000871:Anthelmintics / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D004347:Drug Interactions; D005243:Feces / Q000469:parasitology; D005260:Female; D006188:Haemonchiasis / Q000188:drug therapy / Q000662:veterinary*; D006189:Haemonchus / Q000187:drug effects*; D007559:Ivermectin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007654:Ketoconazole / Q000493:pharmacokinetics*; D008297:Male; D010270:Parasite Egg Count; D011060:Poloxalene / Q000493:pharmacokinetics*; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000469:parasitology; D014018:Tissue Distribution
chemical_list: D018528:ATP-Binding Cassette Transporters; D000871:Anthelmintics; C422648:pluronic block copolymer p85; D007559:Ivermectin; D011060:Poloxalene; D007654:Ketoconazole