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.
Highlights
Cardiovascular diseases are the main cause of a global health burden, with high morbidity and mortality [1,2]
The anti-intrinsic Xase (iXase) method was established for determination of dHG-5 in rat plasma samples
Accuracy and precision deviation of quality control (QC) concentrations were within ±15%, and that of the lower limit of quantification (LLOQ) (0.0625 μg/mL) did not exceed 20%
Summary
Cardiovascular diseases are the main cause of a global health burden, with high morbidity and mortality [1,2]. Their common pathogenesis is thrombosis, the formation of obstructive thrombus, including arterial thromboembolism and venous thromboembolism (VTE) [2]. Anticoagulant is the mainstay treatment for VTE [3], which takes effect by inhibiting coagulation factor(s). UFH exhibits anticoagulant activity by enhancing the effect of antithrombin (AT) in inhibiting activated coagulation factor X (FXa) and thrombin (FIIa), but its pharmacokinetics is unpredictable and clinical monitoring is required [5,6]. The traditional oral anticoagulant warfarin has the defects of unpredictable pharmacokinetics and high bleeding risk [9]
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