Lifschitz Adrian L, Virkel Guillermo L, Sallovitz Juan M, Pis Alejandra, Imperiale Fernanda A, Lanusse Carlos E
Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro, Tandil, Argentina.
J Pharm Pharmacol. 2004 Jan;56(1):61-7. doi: 10.1211/0022357022421.
Ivermectin (IVM) is a broad-spectrum antiparasitic drug extensively used in human and veterinary medicine that is largely excreted in bile and faeces. Loperamide (LPM) is an opioid derivative that reduces gastrointestinal secretions and motility. Both IVM and LPM have been reported to act as P-glycoprotein substrates (P-GP). The goal of the present work was to study the LPM-induced modifications to the pattern of tissue distribution for IVM. Thirty-six Wistar male rats were randomly allocated to two groups (n = 18) and treated subcutaneously with IVM alone or co-administered with LPM. Rats were killed at different times post-treatment and samples (blood and tissues) were collected and analyzed by HPLC. The presence of LPM induced a marked enhancement in the IVM plasma concentrations, resulting in a significantly higher area under concentration time curve (AUC) value (P < 0.01) than that obtained after the administration of IVM alone. Significantly higher IVM availabilities in the liver tissue and small intestine wall (P < 0.05) were obtained in the presence of LPM. There were no statistically significant differences in drug availability in the large intestinal wall after both treatments. However, LPM induced a marked decrease in the amount of IVM recovered in the large intestinal lumen content. The ratio between IVM concentrations in the large intestinal luminal content and plasma at day 1 post-treatment was 4.64-fold higher in the absence of LPM. The delayed intestinal transit time caused by LPM accounting for an extended plasma-intestine recycling time, and a potential competition between IVM and LPM for the P-GP-mediated bile-intestinal secretion processes, may account for the enhanced IVM systemic availability reported in the current study.
伊维菌素（IVM）是一种广泛应用于人类和兽医学的广谱抗寄生虫药物，主要通过胆汁和粪便排泄。洛哌丁胺（LPM）是一种阿片类衍生物，可减少胃肠道分泌物和蠕动。据报道，IVM和LPM均为P-糖蛋白底物（P-GP）。本研究的目的是研究LPM对IVM组织分布模式的影响。将36只雄性Wistar大鼠随机分为两组（n = 18），分别皮下注射单独的IVM或与LPM联合给药。在治疗后的不同时间处死大鼠，收集样本（血液和组织）并通过高效液相色谱法进行分析。LPM的存在导致IVM血浆浓度显著升高，导致浓度-时间曲线下面积（AUC）值显著高于单独给予IVM后获得的值（P < 0.01）。在存在LPM的情况下，肝组织和小肠壁中的IVM可用性显著更高（P < 0.05）。两种治疗后大肠壁中的药物可用性没有统计学显著差异。然而，LPM导致大肠腔内容物中回收的IVM量显著减少。在不存在LPM的情况下，治疗后第1天大肠腔内容物与血浆中IVM浓度的比值高4.64倍。LPM导致的肠道转运时间延迟导致血浆-肠道再循环时间延长，以及IVM和LPM之间对P-GP介导的胆汁-肠道分泌过程的潜在竞争，可能解释了本研究中报道的IVM全身可用性增强的原因。
