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Mar Drugs
2021 Apr 11;194:. doi: 10.3390/md19040212.
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Pharmacokinetics and Pharmacodynamics of a Depolymerized Glycosaminoglycan from Holothuria fuscopunctata, a Novel Anticoagulant Candidate, in Rats by Bioanalytical Methods.
Liu S
,
Zhang T
,
Sun H
,
Lin L
,
Gao N
,
Wang W
,
Li S
,
Zhao J
.
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dHG-5 (Mw 5.3 kD) is a depolymerized glycosaminoglycan from sea cucumber Holothuria fuscopunctata. As a selective inhibitor of intrinsic Xase (iXase), preclinical study showed it was a promising anticoagulant candidate without obvious bleeding risk. In this work, two bioanalytical methods based on the anti-iXase and activated partial thromboplastin time (APTT) prolongation activities were established and validated to determine dHG-5 concentrations in plasma and urine samples. After single subcutaneous administration of dHG-5 at 5, 9, and 16.2 mg/kg to rats, the time to peak concentration (Tmax) was at about 1 h, and the peak concentration (Cmax) was 2.70, 6.50, and 10.11 μg/mL, respectively. The plasma elimination half-life(T1/2β) was also about 1 h and dHG-5 could be almost completely absorbed after s.c. administration. Additionally, the pharmacodynamics of dHG-5 was positively correlated with its pharmacokinetics, as determined by rat plasma APTT and anti-iXase method, respectively. dHG-5 was mainly excreted by urine as the unchanged parent drug and about 60% was excreted within 48 h. The results suggested that dHG-5 could be almost completely absorbed after subcutaneous injection and the pharmacokinetics of dHG-5 are predictable. Studying pharmacokinetics of dHG-5 could provide valuable information for future clinical studies.
81773737 National Natural Science Foundation of China, 81703374 National Natural Science Foundation of China, 2019ZF011-2 Yunnan Provincial Science and Technology Department in China
Figure 1. Plasma concentration-time profile of dHG-5 in rats. Rats were administrated intravenously at 5.20 mg/kg, 9.00 mg/kg, 16.2 mg/kg (a) and subcutaneously at 5.00 mg/kg, 9.00 mg/kg, 16.2 mg/kg (b). The plasma concentration of dHG-5 was calculated by anti-iXase method. Data are expressed as means ± SD (n = 5).
Figure 2. The anticoagulant activity of dHG-5 after i.v. and s.c. administration to rats. Rats were intravenously at 3.00 mg/kg, 5.00 mg/kg and 9.00 mg/kg (a) and subcutaneously at 5.00 mg/kg, 9.00 mg/kg and 16.2 mg/kg (b). Then rat plasma APTT was detected at different time points. Data were expressed as means ± SD (n = 5).
Figure 3. 1H NMR spectra of dHG-5 standard and its metabolites in rat urine. It’s the dHG-5 standard for 1H NMR analysis was dissolved in saline (a) or normal rat urine (b), its metabolites was abstracted from urine of rats treated dHG-5 intravenously (c) or subcutaneously (d). Symbols for assignments are as follows: 1, H4 of Δ4,5GlcA; 2, H1 of internal Fuc3S4S in saccharides chains; 3, H1 of Fuc3S4S at nonreducing terminal; 4, H1 of Fuc linked to terminal alcohol; 5, H4 of internal Fuc; 6, H1 of internal GalNAc and GlcA; 7, other protons on sugar ring; 8, methyl protons in acetyl; 9, H6 of Fuc (Figure S1).
Figure 4. The urine excretion rate of dHG-5 in rats within 48 h. A single dose of dHG-5 was administrated subcutaneously or intravenously. Data are expressed as means ± SD (n = 5).
Alban,
Pharmacokinetic and pharmacodynamic characterization of a medium-molecular-weight heparin in comparison with UFH and LMWH.
2002, Pubmed
Alban,
Pharmacokinetic and pharmacodynamic characterization of a medium-molecular-weight heparin in comparison with UFH and LMWH.
2002,
Pubmed
Balogh,
Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs.
2008,
Pubmed
Baluwala,
Therapeutic monitoring of unfractionated heparin - trials and tribulations.
2017,
Pubmed
Dumaine,
Intravenous low-molecular-weight heparins compared with unfractionated heparin in percutaneous coronary intervention: quantitative review of randomized trials.
2007,
Pubmed
Eikelboom,
New anticoagulants.
2010,
Pubmed
Fonseca,
Fucosylated chondroitin sulfate as a new oral antithrombotic agent.
2006,
Pubmed
,
Echinobase
Gao,
β-Eliminative depolymerization of the fucosylated chondroitin sulfate and anticoagulant activities of resulting fragments.
2015,
Pubmed
,
Echinobase
Gao,
Preparation and characterization of O-acylated fucosylated chondroitin sulfate from sea cucumber.
2012,
Pubmed
,
Echinobase
Gong,
Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation.
2011,
Pubmed
Hirsh,
Guide to anticoagulant therapy: Heparin : a statement for healthcare professionals from the American Heart Association.
2001,
Pubmed
Imanari,
Oral absorption and clearance of partially depolymerized fucosyl chondroitin sulfate from sea cucumber.
1999,
Pubmed
,
Echinobase
Ingrasciotta,
Pharmacokinetics of new oral anticoagulants: implications for use in routine care.
2018,
Pubmed
Laforest,
Pharmacokinetics and biodistribution of technetium 99m labelled standard heparin and a low molecular weight heparin (enoxaparin) after intravenous injection in normal volunteers.
1991,
Pubmed
Lin,
A sensitive and specific HPGPC-FD method for the study of pharmacokinetics and tissue distribution of Radix Ophiopogonis polysaccharide in rats.
2010,
Pubmed
Mingming,
Pharmacokinetics, Tissue Distribution and Excretion Study of Fluoresceinlabeled PS916 in Rats.
2017,
Pubmed
Mischke,
Pharmacokinetics of the low molecular weight heparin dalteparin in cats.
2012,
Pubmed
Pizzi,
Thrombophilias and new oral anticoagulants, a safe alternative to warfarin?
2016,
Pubmed
Pozharitskaya,
Pharmacokinetic and Tissue Distribution of Fucoidan from Fucus vesiculosus after Oral Administration to Rats.
2018,
Pubmed
Raskob,
Thrombosis: a major contributor to global disease burden.
2014,
Pubmed
Sheehan,
Heparin inhibits the intrinsic tenase complex by interacting with an exosite on factor IXa.
2003,
Pubmed
Shikov,
Pharmacokinetics of Marine-Derived Drugs.
2020,
Pubmed
,
Echinobase
Sun,
The components and activities analysis of a novel anticoagulant candidate dHG-5.
2020,
Pubmed
,
Echinobase
Timmis,
European Society of Cardiology: Cardiovascular Disease Statistics 2019.
2020,
Pubmed
Torri,
Heparin centenary - an ever-young life-saving drug.
2016,
Pubmed
Wheeler,
The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy.
2016,
Pubmed
Wu,
Anticoagulant and antithrombotic evaluation of native fucosylated chondroitin sulfates and their derivatives as selective inhibitors of intrinsic factor Xase.
2015,
Pubmed
Yang,
Heparin-activated antithrombin interacts with the autolysis loop of target coagulation proteases.
2004,
Pubmed
Zhao,
Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan.
2015,
Pubmed
Zhou,
Effects of Native Fucosylated Glycosaminoglycan, Its Depolymerized Derivatives on Intrinsic Factor Xase, Coagulation, Thrombosis, and Hemorrhagic Risk.
2020,
Pubmed
,
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