Pharmacokinetics and Pharmacodynamics of a Depolymerized Glycosaminoglycan from Holothuria fuscopunctata,a Novel Anticoagulant Candidate,in Rats by Bioanalytical Methods |
| |
Authors: | Shuang Liu Taocui Zhang Huifang Sun Lisha Lin Na Gao Weili Wang Sujuan Li Jinhua Zhao |
| |
Affiliation: | 1.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; (S.L.); (T.Z.); (H.S.); (L.L.); (W.W.); (S.L.);2.University of Chinese Academy of Sciences, Beijing 100049, China;3.School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China; |
| |
Abstract: | 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. |
| |
Keywords: | pharmacokinetics pharmacodynamics anticoagulant fucosylated glycosaminoglycan dHG-5 method validation |
|
|