Ketoconazole increases the plasma levels of ivermectin in sheep.
The parasiticide ivermectin and the antifungal drug ketoconazole are drugs that interact with P-glycoprotein. We have tested the ability of ketoconazole at a clinical dose to modify the pharmacokinetics of ivermectin in sheep. Lacaune lambs were administered with a single oral dose of ivermectin alone at 0.2 mg/kg (n=5) or in combination with a daily oral dose of ketoconazole (10 mg/kg) given for 3 days before and 2 days after the ivermectin (n=5). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis. Co-administration of ketoconazole induced higher plasma concentrations of ivermectin, leading to a substantial increase in the overall exposure of the animals to the drug. Ketoconazole did not reduce the production of the main ivermectin metabolite but it may rather act by inhibiting P-glycoprotein, and thus increasing the absorption of ivermectin. The use of a P-gp reversing agent such as ketoconazole could be useful tool to optimize antiparasitic therapy in the face of the worldwide development of anthelmintic resistance.
Alvinerie
Michel
M
INRA-Toulouse, UR66 Laboratoire de Pharmacologie-Toxicologie, 180 chemin de Tournefeuille, BP 3, F-31931 Toulouse Cedex 9, France.
Dupuy
Jacques
J
Kiki-Mvouaka
Solange
S
Sutra
Jean-François
JF
Lespine
Anne
A
D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D007559:Ivermectin / Q000097:blood / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012756:Sheep / Q000097:blood*
D000871:Anthelmintics; D000935:Antifungal Agents; D007559:Ivermectin; D007654:Ketoconazole