Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice

Abstract Background: Cutaneous leishmaniasis (CL) is a parasitic disease caused by the protozoan Leishmania spp. Pentavalent antimonial agents have been used as an effective therapy, despite their side effects and resistant cases. Their pharmacokinetics remain largely unexplored. This study aimed to investigate the pharmacokinetic profile of meglumine antimoniate in a murine model of cutaneous leishmaniasis using a radiotracer approach. Methods: Meglumine antimoniate was neutron-irradiated inside a nuclear reactor and was administered once intraperitoneally to uninfected and L. amazonensis-infected BALB/c mice. Different organs and tissues were collected and the total antimony was measured. Results: Higher antimony levels were found in infected than uninfected footpad (0.29% IA vs. 0.14% IA, p = 0.0057) and maintained the concentration. The animals accumulated and retained antimony in the liver, which cleared slowly. The kidney and intestinal uptake data support the hypothesis that antimony has two elimination pathways, first through renal excretion, followed by biliary excretion. Both processes demonstrated a biphasic elimination profile classified as fast and slow. In the blood, antimony followed a biexponential open model. Infected mice showed a lower maximum concentration (6.2% IA/mL vs. 11.8% IA/mL, p = 0.0001), a 2.5-fold smaller area under the curve, a 2.7-fold reduction in the mean residence time, and a 2.5-fold higher clearance rate when compared to the uninfected mice. Conclusions: neutron-irradiated meglumine antimoniate concentrates in infected footpad, while the infection affects antimony pharmacokinetics.

摘要 背景：皮肤利什曼病（Cutaneous leishmaniasis, CL）是由利什曼原虫属（Leishmania spp.）原生动物引发的寄生虫病。五价锑剂虽存在不良反应且耐药病例不断出现，但仍是该病的有效治疗药物，其药代动力学特征目前仍鲜有系统研究。本研究旨在通过放射性示踪剂方法，探究葡甲胺锑（meglumine antimoniate）在皮肤利什曼病小鼠模型中的药代动力学特征。
方法：将葡甲胺锑置于核反应堆内进行中子辐照，随后对未感染及亚马逊利什曼原虫（L. amazonensis）感染的BALB/c小鼠单次腹腔给药。采集不同器官与组织样本，检测总锑含量。
结果：感染组足垫的锑含量显著高于未感染组（0.29%注射剂量 vs. 0.14%注射剂量，p=0.0057），且浓度维持稳定。小鼠肝脏可蓄积并滞留锑，且锑在肝脏中的清除速率较慢。肾脏与肠道的摄取数据支持“锑存在两条消除途径：首先经肾脏排泄，随后经胆道排泄”这一假说，二者均呈现快、慢双相消除特征。血液中锑的代谢符合双指数开放模型。与未感染小鼠相比，感染小鼠的峰浓度更低（6.2%注射剂量/mL vs. 11.8%注射剂量/mL，p=0.0001），药时曲线下面积缩小至原有的2/5，平均驻留时间缩短至原有的1/2.7，清除率升高2.5倍。
结论：经中子辐照的葡甲胺锑可在感染足垫中富集，且感染状态会影响锑的药代动力学特征。