Liu S et al. (2021), Pharmacokinetics and Pharmacodynamics of a Depo...

ECB-ART-49209

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.

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References [+] :

Alban, Pharmacokinetic and pharmacodynamic characterization of a medium-molecular-weight heparin in comparison with UFH and LMWH. 2002, Pubmed

	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).