Pharmacokinetics and tissue distribution of deferoxamine-based nanochelator in rats
Pharmacokinetics and tissue distribution of deferoxamine-based nanochelator in rats
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DOI：
10.2217/nnm-2022-0159
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发表时间：
2022-12-22
期刊：
影响因子：
5.5
通讯作者：
Kim, Jonghan
中科院分区：
文献类型：
--
作者：
Jones, Gregory;Zeng, Lingxue;Kim, Jonghan
铁是一种必需的金属营养素，但过量的铁会产生毒性作用，损害多个器官，包括心脏，肝脏和胰腺。去铁胺（DFO）是美国FDA批准的治疗铁超载的药物，但其使用受到严重不良反应和不方便的每日剂量方案的限制。最近开发的基于DFO的纳米药物（DFO-NP）在治疗动物铁过载方面表现出了希望，并且在动物中更安全。在这种新药可以给予人类之前，必须确定它如何被吸收到体内，在体内加工，并在不同的剂量和剂量途径下从体内清除。在这项研究中，我们测试了DFO-NPs在大鼠静脉注射和皮下注射后的吸收、分布和清除。这项研究表明，DFO-纳米粒子的行为不同，当改变剂量和皮下注射使药物在体内停留时间更长，没有不良反应，这意味着它可以给病人这样的ways.Aim：去铁胺共轭纳米粒子（DFO-纳米粒子），一种新型的纳米螯合剂，用于去除多余的铁的药代动力学特征。材料和方法：在静脉内和皮下给药后，在Sprague-Dawley大鼠中以三种剂量（3.3、10和30 μ mol/kg）评价DFO-NP的药代动力学。结果如下：DFO-NP静脉给药后呈现双相浓度-时间曲线，终末半衰期短（2.0 - 3.2 h），清除率呈剂量依赖性（0.111 - 0.179 l/h/kg），组织分布最小，仅经肾脏排泄，可能存在饱和重吸收机制。皮下给药后，DFO-纳米颗粒表现出吸收速率受限的动力学，具有延长的半衰期（5.7 - 10.1小时）和良好的生物利用度（47 - 107%）。结论：DFO-NP随着剂量的增加表现出非线性的药代动力学，并且皮下给药显著改善了药物暴露，从而使其成为铁螯合的临床可行的给药途径。
Plain language summaryIron is an essential metal nutrient, but excess iron produces toxic effects that damage multiple organs including the heart, liver and pancreas. Deferoxamine (DFO) is a US FDA-approved drug for treating iron overload, but its use is limited by serious adverse effects and an inconvenient daily dose scheme. The recent development of a DFO-based nanomedicine (DFO-NP) has shown promise in treating iron overload in animals and was safer in animals. Before this new drug can be given to humans, how it is absorbed into the body, processed in the body and removed from the body when given in different amounts and dose routes must be determined. In this study, we tested the absorption, distribution and removal of DFO-NPs after intravenous and subcutaneous injection in rats. This study showed that DFO-NPs behave differently when changing the dose and that subcutaneous injection makes the drug stay in the body longer without ill effect, which means it could be given to patients this way.Aim: To characterize the pharmacokinetics of deferoxamine-conjugated nanoparticles (DFO-NPs), a novel nanochelator for removing excess iron. Materials & methods: The pharmacokinetics of DFO-NPs were evaluated in Sprague-Dawley rats at three doses (3.3, 10 and 30 mu mol/kg) after intravenous and subcutaneous administration. Results: DFO-NPs exhibited a biphasic concentration-time profile after intravenous administration with a short terminal half-life (2.0-3.2 h), dose-dependent clearance (0.111-0.179 l/h/kg), minimal tissue distribution and exclusive renal excretion with a possible saturable reabsorption mechanism. DFO-NPs after subcutaneous administration exhibited absorption-rate-limited kinetics with a prolonged half-life (5.7-10.1 h) and favorable bioavailability (47-107%). Conclusion: DFO-NPs exhibit nonlinear pharmacokinetics with increasing dose, and subcutaneous administration substantially improves drug exposure, thereby making it a clinically viable administration route for iron chelation.