Alvinerie Michel, Dupuy Jacques, Kiki-Mvouaka Solange, Sutra Jean-François, Lespine Anne
INRA-Toulouse, UR66 Laboratoire de Pharmacologie-Toxicologie, 180 chemin de Tournefeuille, BP 3, F-31931 Toulouse Cedex 9, France.
Vet Parasitol. 2008 Oct 20;157(1-2):117-22. doi: 10.1016/j.vetpar.2008.06.017. Epub 2008 Jun 22.
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.
抗寄生虫药伊维菌素和抗真菌药酮康唑是与P-糖蛋白相互作用的药物。我们测试了临床剂量的酮康唑改变伊维菌素在绵羊体内药代动力学的能力。给拉库内羔羊单独口服单次剂量的伊维菌素，剂量为0.2 mg/kg（n = 5），或在伊维菌素给药前3天和给药后2天联合每日口服剂量的酮康唑（10 mg/kg）（n = 5）。通过高效液相色谱分析跟踪伊维菌素及其代谢物的血浆动力学15天。酮康唑的共同给药导致伊维菌素的血浆浓度更高，从而使动物对该药物的总体暴露量大幅增加。酮康唑并没有减少主要伊维菌素代谢物的产生，但它可能通过抑制P-糖蛋白起作用，从而增加伊维菌素的吸收。面对全球范围内驱虫抗性的发展，使用酮康唑等P-糖蛋白逆转剂可能是优化抗寄生虫治疗的有用工具。
