Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry.
Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry.
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液相色谱-串联质谱法测定未感染小鼠中抗血吸虫臭氧化铅 OZ418 的药代动力学。
DOI：
10.1128/aac.02394-15
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发表时间：
2016
影响因子：
4.9
通讯作者：
Keiser,Jennifer
中科院分区：
文献类型：
--
作者：
Leonidova,Anna;Vargas,Mireille;Huwyler,Jörg;Keiser,Jennifer
被忽视的主要热带疾病之一血吸虫病目前仅用一种药物吡喹酮进行治疗和控制。由于吡喹酮对血吸虫幼蠕虫缺乏活性，以及担心出现耐药性，因此寻求替代药物。合成的臭氧化物OZ 418对曼氏血吸虫（Schistosoma mansoni）、曼氏血吸虫（S. haematobium和S.但其体内药物分布尚不清楚。为了弥补这一差距，我们的研究确定了未感染小鼠单次口服剂量（400 mg/kg体重）OZ 418的基本药代动力学（PK）参数。首先，根据美国FDA指南，成功开发并验证了一种简单的液相色谱-串联质谱（LC-MS/MS）方法来定量小鼠血浆中的OZ 418浓度。经证明，该方法具有选择性、准确度（93 - 103%）、精密度（5 - 16%）、无显著基质效应（90 - 102%），并提供了极好的回收率（101 - 102%）。给药后2 h（2 - 3 h）达到中位峰浓度190（范围：185 - 231）μg/ml。未经处理的汇总非房室PK分析估计平均血药浓度-时间曲线下面积（AUC）为9，303 μg h/ml（7，039.2 - 11，908.5 μg h/ml），半衰期为38.7 h（20 - 64.6 h）。因此，血浆中的OZ 418水平保持远高于其体外50%抑制浓度（IC 50）27.4 μg/ml（成年S.曼氏蠕虫在72小时）至少75小时。OZ 418在37°C下的降解率很低（121 h内<20%），对细胞色素P450（CYP 450）代谢有微弱的抑制作用（IC 50为37 - 144 μM）。我们的研究结果提供了对OZ 418的处置的第一次洞察，为进一步研究其生物命运和影响铺平了道路。
One of the major neglected tropical diseases, schistosomiasis, is currently treated and controlled with a single drug, praziquantel. The quest for an alternative drug is fueled by the lack of activity of praziquantel against juvenile Schistosoma worms and the fear of emerging resistance. The synthetic ozonide OZ418 has shown high activity against Schistosoma mansoni, S. haematobium, and S. japonicumin vivo, but its drug disposition remains unknown. To bridge this gap, our study determined the basic pharmacokinetic (PK) parameters of a single oral dose (400 mg/kg of body weight) of OZ418 in uninfected mice. First, a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify OZ418 concentrations in mouse plasma was successfully developed and validated according to U.S. FDA guidelines. This method proved to be selective, accurate (93 to 103%), precise (5 to 16%), and devoid of significant matrix effects (90 to 102%) and provided excellent recovery (101 to 102%). A median peak concentration of 190 (range, 185 to 231) μg/ml was reached at 2 h (2 to 3 h) posttreatment. A naive pooled noncompartmental PK analysis estimated a mean area under the plasma concentration-versus-time curve (AUC) of 9,303 μg h/ml (7,039.2 to 11,908.5 μg h/ml) and a half-life of 38.7 h (20 to 64.6 h). Thus, the OZ418 level in plasma remained well above itsin vitro50% inhibitory concentrations (IC50s) of 27.4 μg/ml (adult S. mansoni worms at 72 h) for at least 75 h. Consistently, OZ418 degraded little in plasma at 37°C (<20% in 121 h) and weakly inhibited cytochrome P450 (CYP450) metabolism (IC50of 37 to 144 μM). Our results provide a first insight into the disposition of OZ418, paving the way for further studies of its biological fate and effect.