Investigation of the pharmacokinetic properties of synthetic heparan sulfate oligosaccharides.
Investigation of the pharmacokinetic properties of synthetic heparan sulfate oligosaccharides.
复制标题
合成硫酸乙酰肝素寡糖的药代动力学特性的研究。
DOI：
10.1093/glycob/cwac068
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发表时间：
2023
期刊：
影响因子：
4.3
通讯作者：
Liu,Jian
中科院分区：
文献类型：
--
作者：
Arnold,Katelyn;Wang,Zhangjie;Lucas,Andrew;Zamboni,William;Xu,Yongmei;Liu,Jian
硫酸乙酰肝素(HS)是一种具有广泛生物活性的硫酸化多糖。人们对结构均一的HS寡糖作为治疗药物的开发越来越感兴趣。然而，影响HS类药物药代动力学特性的因素仍不清楚。在这里，我们报告了一组具有不同硫酸盐化模式的十二糖(12-MERS)在健康小鼠中的药代动力学特性，并揭示了一种十八糖(18-mer)在急性损伤小鼠中的药代动力学特性。在12聚体中，112聚体是抗凝剂，被称为地卡肝素，3 12-聚体是非抗凝剂。血浆和尿液中12-MERS的浓度用液相色谱-串联质谱法进行双糖分析。我们在12聚体平板上观察到抗凝剂和非抗凝寡糖之间的显著差异，显示抗凝剂去肝素的清除速度是非抗凝剂12-MERS的4.6倍至8.6倍，血浆暴露时间是非抗凝剂12-MERS的4.4倍至8倍。我们还观察到HS寡糖的清除受到疾病的影响。使用抗炎18-聚体，我们发现在肝功能衰竭小鼠模型中，与健康小鼠相比，18-聚体的清除减少了2.8倍。我们的结果表明，如果低聚糖与循环蛋白的相互作用较低，它们在肾脏内会被迅速清除。我们观察到，低聚糖的清除率与与靶蛋白的结合程度成反比，这可能会因病理生理条件的不同而不同。我们的发现揭示了血浆和肾脏低聚糖清除的一个促成因素，这将有助于基于HS的疗法的发展。
Heparan sulfate (HS) is a sulfated polysaccharide with a wide range of biological activities. There is an increasing interest in the development of structurally homogeneous HS oligosaccharides as therapeutics. However, the factors influencing the pharmacokinetic properties of HS-based therapeutics remain unknown. Here, we report the pharmacokinetic properties of a panel of dodecasaccharides (12-mers) with varying sulfation patterns in healthy mice and uncover the pharmacokinetic properties of an octadecasaccharide (18-mer) in acutely injured mice. In the 12-mer panel, 1 12-mer, known as dekaparin, is anticoagulant, and 3 12-mers are nonanticoagulant. The concentrations of 12-mers in plasma and urine were determined by the disaccharide analysis using liquid chromatography coupled with tandem mass spectrometry. We observed a striking difference between anticoagulant and nonanticoagulant oligosaccharides in the 12-mer panel, showing that anticoagulant dekaparin had a 4.6-fold to 8.6-fold slower clearance and 4.4-fold to 8-fold higher plasma exposure compared to nonanticoagulant 12-mers. We also observed that the clearance of HS oligosaccharides is impacted by disease. Using an antiinflammatory 18-mer, we discovered that the clearance of 18-mer is reduced 2.8-fold in a liver failure mouse model compared to healthy mice. Our results suggest that oligosaccharides are rapidly cleared renally if they have low interaction with circulating proteins. We observed that the clearance rate of oligosaccharides is inversely associated with the degree of binding to target proteins, which can vary in response to pathophysiological conditions. Our findings uncover a contributing factor for the plasma and renal clearance of oligosaccharides which will aid the development of HS-based therapeutics.