Ketoconazole increases the plasma levels of ivermectin in sheep |
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Authors: | Alvinerie Michel Dupuy Jacques Kiki-Mvouaka Solange Sutra Jean-François Lespine Anne |
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Institution: | INRA-Toulouse, UR66 Laboratoire de Pharmacologie-Toxicologie, 180 chemin de Tournefeuille, BP 3, F-31931 Toulouse Cedex 9, France. |
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Abstract: | 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 0.2mg/kg (n=5) or in combination with a daily oral dose of ketoconazole (10mg/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. |
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