title: Multiple oral dosing of ketoconazole increases dog exposure to ivermectin.
abstract: OBJECTIVE
  The parasiticide ivermectin and the antimicrobial drug ketoconazole are macrolides that interact with P-glycoprotein. We investigated the effects of ketoconazole at a clinical dose on the pharmacokinetics of ivermectin, a CYP3A substrate with low hepatic clearance.
  
  
  METHODS
  Beagle dogs received a single subcutaneous injection of ivermectin at 0.05 mg/kg alone (n=6) or in combination with a daily oral dose of ketoconazole 10 mg/kg over 5 days before and after ivermectin administration (n=6). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis.
  
  
  RESULTS
  Co-administered ketoconazole induced a higher plasma concentration and longer residence time of ivermectin in dogs, leading to a substantial increase in the overall exposure of the animal to the drug. Ketoconazole does not interfere with the production of the ivermectin metabolite but it may rather inhibit the elimination of the parental drug by interfering with P-gp transport.
  
  
  CONCLUSIONS
  Multiple oral dosing of ketoconazole dramatically altered the pharmacokinetics of ivermectin in dogs leading to an increase in systemic exposure to the drug. Neurotoxicity of ivermectin means that inhibition of the P-gp function at the blood-brain barrier during polytherapy using P-gp inhibitors must be taken into consideration.
authors.affiliation: Clinique Vétérinaire des Lavandes, 26160 La Begude de Mazenc, France. INRA-UR66, Laboratoire de Pharmacologie-Toxicologie, BP 3, 31931 Toulouse Cedex 9, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hugnet
authors.forename: Anne
authors.initials: A
authors.lastname: Lespine
authors.forename: Michel
authors.initials: M
authors.lastname: Alvinerie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004334:Drug Administration Schedule / Q000662:veterinary; D004347:Drug Interactions; D007279:Injections, Subcutaneous / Q000662:veterinary; D007559:Ivermectin / Q000009:adverse effects / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D020258:Neurotoxicity Syndromes; D011897:Random Allocation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D000977:Antiparasitic Agents; D007559:Ivermectin; D007654:Ketoconazole