Pharmacokinetics and Pharmacodynamics of a Depolymerized Glycosaminoglycan from <i>Holothuria fuscopunctata</i>, a Novel Anticoagulant Candidate, in Rats by Bioanalytical Methods
2021
Shuang Liu | Taocui Zhang | Huifang Sun | Lisha Lin | Na Gao | Weili Wang | Sujuan Li | Jinhua Zhao
dHG-5 (Mw 5.3 kD) is a depolymerized glycosaminoglycan from sea cucumber <i>Holothuria fuscopunctata</i>. 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 (<i>T<sub>max</sub></i>) was at about 1 h, and the peak concentration (<i>C<sub>max</sub></i>) was 2.70, 6.50, and 10.11 μg/mL, respectively. The plasma elimination half-life(<i>T<sub>1/2</sub><sub>β</sub></i>) 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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