吸入性颗粒物的肺部递送后“ Piner治疗性” Nitazoxanide在小鼠中的药代动力学，代谢和部分生物分布,Molecular Pharmaceutics

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吸入性颗粒物的肺部递送后“ Piner治疗性” Nitazoxanide在小鼠中的药代动力学，代谢和部分生物分布
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-03-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b01089
Anuradha Gupta ₁ , Sachin L. Tulsankar ₁ , Rabi S. Bhatta ₁ , Amit Misra ₁

Affiliation

Nitazoxanide（NTZ）在哺乳动物细胞中诱导自噬，并且对宿主以及病原体也具有分枝杆菌杀灭活性，显示出两管齐下的治疗效果。研究了吸入的NTZ的药代动力学和生物分布。通过喷雾干燥制备PLGA基质中的含NTZ的颗粒。HPLC和LC-MS / MS方法得到了开发和验证。将颗粒作为吸入剂给予小鼠。在不同时间点估计血浆和组织中的药物浓度。通过HPLC令人满意地评估了药物载量（约36％），包封率（> 90％）以及NTZ在血浆和肺匀浆中的转化为代谢产物。通过LC-MS确定静脉内给药或吸入后NTZ的药代动力学和生物分布。NTZ转化为噻唑烷（30分钟内达到99％）和其他代谢物。捕获在颗粒中的NTZ的肺部递送可将药物在血浆，肺组织和肺泡巨噬细胞中的半衰期分别提高3倍，12倍和200倍。与静脉内给药相比，在肺部递送时观察到靶向递送和延长的肺滞留以及肾脏的剂量节省。

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Pharmacokinetics, Metabolism, and Partial Biodistribution of “Pincer Therapeutic” Nitazoxanide in Mice following Pulmonary Delivery of Inhalable Particles

Nitazoxanide (NTZ) induces autophagy in mammalian cells and also has mycobactericidal activity, displaying a two-pronged therapeutic effect, on the host as well as the pathogen. The pharmacokinetics and biodistribution of inhaled NTZ were investigated. Particles containing NTZ in a matrix of PLGA were prepared by spray drying. HPLC and LC–MS/MS methods were developed and validated. Particles were administered as inhalations to mice. Drug concentrations in plasma and tissues were estimated at different time points. Drug loading (∼36%), entrapment efficiency (>90%), and the conversion of NTZ into metabolites in plasma and lung homogenates were assessed satisfactorily by HPLC. NTZ pharmacokinetics and biodistribution following intravenous administration or inhalation were established by LC–MS. NTZ converted into tizoxanide (99% in 30 min) and other metabolites. Pulmonary delivery of NTZ entrapped in particles increased the half-life of the drug by factors of 3, 12, and 200 in the plasma, lung tissue, and alveolar macrophages, respectively. Targeted delivery and prolonged lung retention along with dose sparing of the kidneys was observed upon pulmonary delivery as compared to intravenous administration.

更新日期：2017-03-14

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