经静脉注射 14C-WLBU2 后单次给药于小鼠的工程化阳离子抗菌肽 WLBU2 的质量平衡研究。
Mass Balance Study of the Engineered Cationic Antimicrobial Peptide, WLBU2, Following a Single Intravenous Dose of 14C-WLBU2 in Mice.
机构信息
Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Ave. Pittsburgh, PA15213, United States.
Department of Medicine Renal-Electrolyte Division, University of Pittsburgh School of Medicine, 3550 Terrace Street. Pittsburgh, PA15261, United States.
出版信息
Curr Rev Clin Exp Pharmacol. 2021;16(3):263-272. doi: 10.2174/1574884715666200810094201.
BACKGROUND
To address multidrug resistance, we developed engineered Cationic Antimicrobial Peptides (eCAPs). Lead eCAP WLBU2 displays potent activity against drug-resistant bacteria and effectively treats lethal bacterial infections in mice, reducing bacterial loads to undetectable levels in diverse organs.
OBJECTIVE
To support the development of WLBU2, we conducted a mass balance study.
METHODS
CD1 mice were administered 10, 15, 20 and 30 mg/kg of QDx5 WLBU2 or a single dose of [14C]-WLBU2 at 15 mg/kg IV. Tolerability, tissue distribution and excretion were evaluated with liquid scintillation and HPLC-radiochromatography.
RESULTS
The maximum tolerated dose of WLBU2 is 20 mg/kg IV. We could account for greater than >96% of the radioactivity distributed within mouse tissues at 5 and 15 min. By 24h, only ~40-50% of radioactivity remained in the mice. The greatest % of the dose was present in liver, accounting for ~35% of radioactivity at 5 and 15 min, and ~ 8% of radioactivity remained at 24h. High radioactivity was also present in kidneys, plasma, red blood cells and lungs, while less than 0.2% of radioactivity was present in brain, fat, or skeletal muscle. Urinary and fecal excretion accounted for 12.5 and 2.2% of radioactivity at 24h.
CONCLUSION
WLBU2 distributes widely to mouse tissues and is rapidly cleared with a terminal radioactivity half-life of 22 h, a clearance of 27.4 mL/h/kg, and a distribution volume of 0.94 L/kg. At 2-100 μg-eq/g, the concentrations of 14C-WLBU2 appear high enough in the tissues to account for the inhibition of microbial growth.
背景
为了解决多药耐药性问题，我们开发了工程化阳离子抗菌肽（eCAP）。先导 eCAP WLBU2 对耐药菌具有强大的活性，并能有效治疗小鼠致命性细菌感染，将各种器官中的细菌负荷降低至无法检测的水平。
目的
为了支持 WLBU2 的开发，我们进行了一项物料平衡研究。
方法
CD1 小鼠静脉注射 10、15、20 和 30mg/kg 的 QDx5 WLBU2 或 15mg/kg 的单剂量[14C]-WLBU2。采用液体闪烁法和 HPLC-放射性色谱法评估耐受性、组织分布和排泄情况。
结果
WLBU2 的最大耐受剂量为 20mg/kg 静脉注射。在 5 和 15 分钟时，我们可以解释分布在小鼠组织内的放射性物质的>96%。24 小时时，只有约 40-50%的放射性物质留在小鼠体内。最大剂量的放射性物质存在于肝脏中，在 5 和 15 分钟时占放射性物质的35%，24 小时时仍有8%的放射性物质存在。放射性物质在肾脏、血浆、红细胞和肺中含量较高，而在大脑、脂肪或骨骼肌中的含量不到 0.2%。尿液和粪便排泄占 24 小时时放射性物质的 12.5%和 2.2%。
结论
WLBU2 广泛分布于小鼠组织中，并迅速清除，放射性半衰期为 22 小时，清除率为 27.4mL/h/kg，分布容积为 0.94L/kg。在 2-100μg-eq/g 时，14C-WLBU2 浓度在组织中足够高，足以解释微生物生长的抑制作用。
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