糖胺聚糖寡糖HS14定量分析方法的建立及其药代动力学研究

	糖胺聚糖寡糖HS14定量分析方法的建立及其药代动力学研究; Establishment of quantitative analysis methods of glycosaminoglycan oligosaccharide HS14 and its pharmacokinetic study
	张桃翠
导师	赵金华
摘要	Glycosaminoglycan oligosaccharide HS14 was a pure oligosaccharide prepared by depolymerization of fucosylated glycosaminoglycan (FG) which was extracted from sea cucumber Holothuria fuscopunctata, with a molecular weight of 4373 Da. Our group found that dHG-5, a homogeneous mixture of glycosaminoglycan oligosaccharides, could not only selectively act on intrinsic factor Xase (iXase) but also have strong anticoagulant activity in vitro and in vivo. As a new anticoagulant candidate, dHG-5 is now in the late preclinical stage. The overall pharmacokinetic characteristics of dHG-5 as an oligosaccharide mixture have been clarified in the previous work. However, pharmacokinetic characteristics of each oligosaccharide contained in dHG-5 remain unclear. Accurate analyzation of the pharmacokinetic characteristics of pure oligosaccharides was helpful to the correlations between a pure oligosaccharide and the mixture of oligosaccharides. The anticoagulant activity of pure oligosaccharide HS14 and HS17 contained in dHG-5 was similar to that of dHG-5, and the proportion of HS14 in dHG-5 was relatively high, therefore quantitative analysis methods were established and validated to determine HS14 concentrations in rat plasma and urine samples and the pharmacokinetics of HS14 was preliminary studied in this work. Both of the two methods were of bioanalytical methods with better security which could provide reference information for clinical trials. The main contents and results of this work were as follows: (1) Establishment and validation of anti-intrinsic factor Xase (anti-iXase) method of HS14 in rat plasma samples. The anti-iXase method met the requirements for in vivo quantitative analysis of biological samples, and this method could be applied to detect the drug concentrations of HS14 in rat plasma. (2) Establishment and validation of APTT prolongation method of HS14 in rat urine samples. APTT prolongation method met the requirements for in vivo quantitative analysis of biological samples, and this method could be applied to detect the drug concentrations of HS14 in rat urine. (3) The anti-iXase method and APTT prolongation method were applied to determine HS14 concentrations in rat plasma and urine samples in order to have a preliminary understanding of HS14 about the absorption and excretion after subcutaneous or intravenous administration to rats. HPLC and NMR methods were used to metabolite identification of HS14. Absolute bioavailability of HS14 subcutaneously administrated were 59.7%, 84.3% and 77.7%, respectively, indicating that HS14 could be absorbed after s.c. administration with good bioavailability. These results indicated that the elimination of HS14 belongs to a first-order linear kinetics. After i.v. or s.c. administration of HS14, the metabolite was considered as the unchanged parent drug by urine. The cumulative excretion rates of HS14 after i.v. and s.c. administration were 67.06% and 78.94 %.
	2021-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74590
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	张桃翠. 糖胺聚糖寡糖HS14定量分析方法的建立及其药代动力学研究, Establishment of quantitative analysis methods of glycosaminoglycan oligosaccharide HS14 and its pharmacokinetic study[D],2021.

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