Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor

doi:10.1016/j.thromres.2024.109041

KIB OpenIR

	Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor
	Zhang, Taocui; Lin, Lisha; Ren, Lin; Sun, Huifang; Wang, Weili; Liu, Shuang; Li, Shanni; Xiao, Chuang; Gao, Na; Zhao, Jinhua
	2024
发表期刊	THROMBOSIS RESEARCH
ISSN	0049-3848
卷号	240 页码:109041
摘要	The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi -component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc 3S4S -alpha(1,3)-L- Delta 4,5 GlcA- alpha(1,3)-{D-GalNAc 4S6S - beta (1,4)-[L-Fuc 3S4S -alpha(1,]3)-D-GlcA- beta (1,3)-} 3 -D-GalNAc 4S6S - beta (1,4)-[L-Fuc 3S4S -alpha(1,]3)-D- GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %-80.9 % determined by the validated bioanalytical methods. The maximum concentration ( C max ) was 3.73, 8.07, and 11.95 mu g/mL, respectively, and the time reaching C max ( T max ) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first -order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.
DOI	10.1016/j.thromres.2024.109041
WOS记录号	WOS:001249540100001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/76400
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Zhang, Taocui,Lin, Lisha,Ren, Lin,et al. Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor[J]. THROMBOSIS RESEARCH,2024,240:109041.
APA	Zhang, Taocui.,Lin, Lisha.,Ren, Lin.,Sun, Huifang.,Wang, Weili.,...&Zhao, Jinhua.(2024).Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor.THROMBOSIS RESEARCH,240,109041.
MLA	Zhang, Taocui,et al."Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor".THROMBOSIS RESEARCH 240(2024):109041.

条目包含的文件		下载所有文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
10.1016_j.thromres.2（3194KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	浏览下载