Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, UNCPBA, Campus Universitario, 7000 Tandil, Argentina.
Exp Parasitol. 2010 Jun;125(2):172-8. doi: 10.1016/j.exppara.2010.01.009. Epub 2010 Jan 28.
The role of the drug efflux pump, known as P-glycoprotein, in the pharmacokinetic disposition (host) and resistance mechanisms (target parasites) of the macrocyclic lactone (ML) antiparasitic compounds has been demonstrated. To achieve a deeper comprehension on the relationship between their pharmacokinetic and pharmacodynamic behaviors, the aim of the current work was to assess the comparative effect of loperamide, a well-established P-glycoprotein modulator, on the ivermectin and moxidectin disposition kinetics and efficacy against resistant nematodes in cattle. Fifty (50) Aberdeen Angus male calves were divided into five (5) experimental groups. Group A remained as an untreated control. Animals in the other experimental Groups received ivermectin (Group B) and moxidectin (Group C) (200 microg/kg, subcutaneously) given alone or co-administered with loperamide (0.4 mg/kg, three times every 24 h) (Groups D and E). Blood samples were collected over 30 days post-treatment and drug plasma concentrations were measured by HPLC with fluorescence detection. Estimation of the anthelmintic efficacy for the different drug treatments was performed by the faecal egg count reduction test (FECRT). Nematode larvae were identified by pooled faecal cultures for each experimental group. Cooperia spp. and Ostertagia spp. were the largely predominant nematode larvae in pre-treatment cultures. A low nematodicidal efficacy (measured by the FECRT) was observed for both ivermectin (23%) and moxidectin (69%) in cattle, which agrees with a high degree of resistance to both molecules. Cooperia spp. was the most abundant nematode species recovered after the different drug treatments. The egg output reduction values increased from 23% to 50% (ivermectin) and from 69% to 87% (moxidectin) following their co-administration with loperamide. Enhanced systemic concentrations and an altered disposition of both ML in cattle, which correlates with a tendency to increased anthelmintic efficacy, were observed in the presence of loperamide. Overall, the in vivo modulation of P-glycoprotein activity modified the kinetic behavior and improved the efficacy of the ML against resistant nematodes in cattle. The work provides further evidence on the high degree of resistance to ML in cattle nematodes and, shows for the first time under field conditions, that modulation of P-glycoprotein may be a valid pharmacological approach to improve the activity and extend the lifespan of these antiparasitic molecules.
已经证明，药物外排泵（称为 P-糖蛋白）在大环内酯类（ML）抗寄生虫化合物的药代动力学处置（宿主）和耐药机制（靶寄生虫）中发挥作用。为了更深入地了解它们的药代动力学和药效学行为之间的关系，本研究的目的是评估洛哌丁胺（一种成熟的 P-糖蛋白调节剂）对伊维菌素和莫昔克丁在牛体内的药代动力学和疗效的比较影响，以抵抗耐药线虫。将 50 只（50）阿伯丁安格斯雄性小牛分为五（5）个实验组。A 组作为未处理的对照组。其他实验组的动物分别接受伊维菌素（B 组）和莫昔克丁（C 组）（200μg/kg，皮下）单独或与洛哌丁胺（0.4mg/kg，每天三次，每 24 小时一次）（D 和 E 组）共同给药。在治疗后 30 天内采集血样，并通过 HPLC 荧光检测法测量药物血浆浓度。通过粪便卵计数减少试验（FECRT）评估不同药物处理的驱虫效果。通过每组的混合粪便培养鉴定线虫幼虫。在预处理培养物中，主要是旋毛虫和 ostertagia 幼虫。牛对伊维菌素（23%）和莫昔克丁（69%）的驱虫效果较低，这与对这两种分子的高度耐药性一致。在不同药物处理后，回收的线虫幼虫数量最多的是旋毛虫。洛哌丁胺联合使用后，伊维菌素的卵排出减少值从 23%增加到 50%（伊维菌素），莫昔克丁从 69%增加到 87%。在洛哌丁胺存在下，观察到 ML 在牛体内的系统浓度增强和分布方式改变，这与驱虫效果增加的趋势相关。总之，P-糖蛋白活性的体内调节改变了 ML 的动力学行为，并提高了它们对牛耐药线虫的疗效。该研究进一步证明了牛线虫对 ML 的高度耐药性，并首次在现场条件下表明，P-糖蛋白的调节可能是一种有效的药理学方法，以提高这些驱虫分子的活性和延长其寿命。
