Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs
Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs
复制标题
DOI：
10.1124/dmd.110.034827
复制
发表时间：
2011-05-01
影响因子：
3.9
通讯作者：
Locuson, Charles W.
中科院分区：
文献类型：
--
作者：
Dunn, Stewart T.;Hedges, Laura;Locuson, Charles W.
在狗身上观察到了与伊维菌素毒性一致的神经副作用，当大剂量的常见心线虫防治剂伊维菌素与口服跳蚤防治剂多杀菌素联合使用时。基于大量报道表明，ATP结合盒药物转运体P-糖蛋白(P-gp)在犬体内伊维菌素外排中所起的作用，进行了一项体内研究，以确定伊维菌素毒性是否是与多杀菌素的药代动力学相互作用的结果。将Beagle犬随机分为3组：治疗1组(T01)给予伊维菌素(60 mU g/kg)，治疗2组(T02)给予多杀菌素(30 mg/kg)，治疗3组(T03)同时给予伊维菌素和多杀菌素。在伊维菌素存在的情况下，多杀菌素的药代动力学没有改变，而伊维菌素的血浆药代动力学显示，当伊维菌素与多杀菌素联合应用时，曲线下面积显著增加(是对照的3.6倍)。大多数相互作用被认为是由于抑制了肠道和/或肝脏P-gp介导的伊维菌素分泌途径。此外，体外Transwell实验显示，转人多药耐药基因1的Madin-Darby犬肾II细胞株在不同浓度下呈极化外流。
Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P-glycoprotein (P-gp) in ivermectin efflux in dogs, an in vivo study was conducted to determine whether ivermectin toxicity results from a pharmacokinetic interaction with spinosad. Beagle dogs were randomized to three groups treated orally in parallel: Treatment group 1 (T01) received ivermectin (60 mu g/kg), treatment group 2 (T02) received spinosad (30 mg/kg), and treatment group 3 (T03) received both ivermectin and spinosad. Whereas spinosad pharmacokinetics were unchanged in the presence of ivermectin, ivermectin plasma pharmacokinetics revealed a statistically significant increase in the area under the curve (3.6-fold over the control) when ivermectin was coadministered with spinosad. The majority of the interaction is proposed to result from inhibition of intestinal and/or hepatic P-gp-mediated secretory pathways of ivermectin. Furthermore, in vitro Transwell experiments with a human multidrug resistance 1-transfected Madin-Darby canine kidney II cell line showed polarized efflux at concentrations