Laboratorio de Parasitología, Instituto Nacional de Tecnología Agropecuaria (INTA), Estación Experimental Balcarce, Balcarce 7620, Argentina.
Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET, Facultad de Ciencias Veterinarias, UNCPBA, Campus Universitario, 7000 Tandil, Argentina.
Int J Parasitol Drugs Drug Resist. 2012 Dec 3;3:20-7. doi: 10.1016/j.ijpddr.2012.11.001. eCollection 2013 Dec.
The high level of resistance to the macrocyclic lactones has encouraged the search for strategies to optimize their potential as antiparasitic agents. There is a need for pharmaco-parasitological studies addressing the kinetic-dynamic differences between various macrocyclic lactones under standardized in vivo conditions. The current work evaluated the relationship among systemic drug exposure, target tissue availabilities and the pattern of drug accumulation within resistant Haemonchus contortus for moxidectin, abamectin and ivermectin. Drug concentrations in plasma, target tissues and parasites were measured by high performance liquid chromatography. Additionally, the efficacy of the three molecules was evaluated in lambs infected with resistant nematodes by classical parasitological methods. Furthermore, the comparative determination of the level of expression of P-glycoprotein (P-gp2) in H. contortus recovered from lambs treated with each drug was performed by real time PCR. A longer persistence of moxidectin (P < 0.05) concentrations in plasma was observed. The concentrations of the three compounds in the mucosal tissue and digestive contents were significant higher than those measured in plasma. Drug concentrations were in a range between 452 ng/g (0.5 day post-treatment) and 32 ng/g (2 days post-treatment) in the gastrointestinal (GI) contents (abomasal and intestinal). Concentrations of the three compounds in H. contortus were in a similar range to those observed in the abomasal contents (positive correlation P = 0.0002). Lower moxidectin concentrations were recovered within adult H. contortus compared to abamectin and ivermectin at day 2 post-treatment. However, the efficacy against H. contortus was 20.1% (ivermectin), 39.7% (abamectin) and 89.6% (moxidectin). Only the ivermectin treatment induced an enhancement on the expression of P-gp2 in the recovered adult H. contortus, reaching higher values at 12 and 24 h post-administration compared to control (untreated) worms. This comparative pharmacological evaluation of three of the most used macrocyclic lactones compounds provides new insights into the action of these drugs.
大环内酯类药物的高水平耐药性促使人们寻求策略来优化其作为抗寄生虫药物的潜力。有必要进行药物-寄生虫动力学研究，以解决各种大环内酯类药物在标准化体内条件下的动力学-动态差异。本研究评估了系统药物暴露、靶组织可利用性以及在耐药捻转血矛线虫体内药物积累模式之间的关系，研究药物为莫昔克丁、阿维菌素和伊维菌素。通过高效液相色谱法测定血浆、靶组织和寄生虫中的药物浓度。此外，还通过经典寄生虫学方法评估了这三种分子在感染耐药线虫的羔羊中的疗效。此外，还通过实时 PCR 比较测定了从用每种药物治疗的羔羊中回收的捻转血矛线虫中 P 糖蛋白（P-gp2）表达水平。莫昔克丁（P < 0.05）在血浆中的浓度持续时间更长。三种化合物在黏膜组织和消化内容物中的浓度明显高于血浆中的浓度。在胃肠道（GI）内容物（皱胃和肠道）中，药物浓度在 452ng/g（治疗后 0.5 天）和 32ng/g（治疗后 2 天）之间（abomasal and intestinal）。在捻转血矛线虫中，三种化合物的浓度与皱胃内容物中的浓度相似（正相关 P = 0.0002）。与阿维菌素和伊维菌素相比，莫昔克丁在治疗后第 2 天在成年捻转血矛线虫中回收的浓度较低。然而，对捻转血矛线虫的疗效分别为 20.1%（伊维菌素）、39.7%（阿维菌素）和 89.6%（莫昔克丁）。只有伊维菌素处理诱导回收的成年捻转血矛线虫中 P-gp2 的表达增强，在给药后 12 和 24 小时与对照（未处理）蠕虫相比达到更高的值。对三种最常用的大环内酯类化合物的这种比较药理学评估为这些药物的作用提供了新的见解。
