Tissue Penetration of a Novel Spectinamide Antibiotic for the Treatment of Tuberculosis
Tissue Penetration of a Novel Spectinamide Antibiotic for the Treatment of Tuberculosis
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DOI：
10.1208/s12248-016-9900-7
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发表时间：
2016-05-01
期刊：
影响因子：
4.5
通讯作者：
Meibohm, Bernd
中科院分区：
文献类型：
--
作者：
Madhura, Dora Babu;Trivedi, Ashit;Meibohm, Bernd
研究了具有抗结核活性的新型丁酰胺抗生素1329的体内生物分布和药代动力学，并对其进行了连续9次、12小时静脉给药。在第一次和第八次给药后连续采集血液样本，在第9次给药后1 h采集主要器官和组织。在整个给药期间监测尿液和粪便排泄情况。用闪烁计数法评估所收集样品的放射性。在治疗过程中，86.6%的放射性物质在尿液、粪便、器官和肌肉组织中被恢复。尿排泄是主要的清除途径，70%的放射性从尿液中回收，12.6%从粪便中回收。第一次给药和第8次给药后2小时血清放射性时间谱相同，Cmax （3.39 vs. 3.55 mCi/L）和AUC0-tau （5.08 vs. 5.17 mCi/欧分h/L）相似，表明多次给药期间1329没有大量积累。肺结核感染的主要靶器官肺和脾的放射性分别是血液的2.79倍和3.06倍。同样，巨噬细胞对1329的细胞内摄取比链霉素高6倍。总的来说，这些观察结果表明生物分布特性有利于靶向肺结核感染。
The in vivo biodistribution and pharmacokinetics of 1329, a novel spectinamide antibiotic with anti-tubercular activity, were studied during intravenous administration of an tritium-labeled compound for nine consecutive, 12-hourly doses to rats. Serial blood samples were collected after the first and the eighth dose, and major organs and tissues were collected 1 h after the ninth dose. Urinary and fecal excretion was monitored throughout the dosing period. Radioactivity in the collected samples was assessed by scintillation counting. During the course of treatment, 86.6% of the administered radioactivity was recovered in urine, feces, organs, and muscle tissue. Urinary excretion was the major route of elimination, with 70% of radioactivity recovered from urine and 12.6% from feces. The time profiles of radioactivity in serum after the first and the eighth dose were identical for the first 2 h post-dose, with similar Cmax (3.39 vs. 3.55 mCi/L) and AUC0-tau (5.08 vs. 5.17 mCi aEuro cent h/L), indicating no substantial accumulation of 1329 during multiple dosing. Radioactivity in major target organs for pulmonary tuberculosis infection, the lungs and spleen, was 2.79- and 3.06-fold higher than in the blood. Similarly, the intracellular uptake of 1329 into macrophages was sixfold higher than for streptomycin. Overall, these observations suggest biodistribution properties favorable for targeting pulmonary tuberculosis infections.