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Research Area
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Description
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Venous thromboembolism, Stroke |
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Biological Activity
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Description
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Apixaban is a highly selective, reversible inhibitor of Factor Xa with Ki of 0.08 nM and 0.17 nM in human and rabbit, respectively. |
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Targets
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Human Factor Xa |
Rabbit Factor Xa |
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IC50 |
0.08 nM (Ki) |
0.17 nM (Ki) [1] |
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In Vitro
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Apixaban exhibits a high degree of potency, selectivity, and efficacy on Factor Xa with Ki of 0.08 nM and 0.17 nM for Human Factor Xa and Rabbit Factor Xa, respectively. [1] In vitro, Apixaban prolongs the clotting times of normal human plasma with the concentrations (EC2x) of 3.6 μM, 0.37 μM, 7.4 μM, and 0.4 μM, which are required respectively to double the prothrombin time (PT), modified prothrombin time (mPT), activated partial thromboplastin time (APTT) and HepTest. Besides, Apixaban shows the highest potency in human and rabbit plasma, but less potency in rat and dog plasma in both the PT and APTT assays. [2] |
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In Vivo
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In the dog, Apixaban shows the excellent pharmacokinetics with very low clearance (Cl: 0.02 L kg-1 h-1), and low volume of distribution (Vdss: 0.2 L kg-1). Besides, Apixaban also exhibits a moderate half-life (T1/2: 5.8 hours) and good oral bioavailability (F: 58%). [1] In the arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT) and electrically mediated carotid arterial thrombosis (ECAT) rabbit models, Apixaban produces dose-dependent antithrombotic effects with EC50 of 270 nM, 110 nM and 70 nM, respectively. [2] Apixaban significantly inhibits factor Xa activity with IC50 of 0.22 μM in rabbit ex vivo. [3] In chimpanzee, Apixaban also shows small volume of distribution (Vdss: 0.17 L kg-1), low systemic clearance (Cl: 0.018 L kg-1 h-1), and good oral bioavailability (F: 59%). [4] |
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Clinical Trials
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Apixaban is currently in Phase III clinical trials for the Prevention of Thrombosis-related Events in Patients With Acute Medical Illness. |
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Features
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Apixaban is a highly selective, reversible, and direct factor Xa inhibitor . |
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Protocol
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Kinase Assay
[1]
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| Enzyme Affinity Assays. |
All enzyme Ki values are obtained from purified human enzymes. All fXa assays are run in microtiter plates using a total volume of 250 μL in 0.1 M sodium phosphate buffer containing 0.2 M NaCl and 0.5% polyethylene glycol 6000 at pH 7.0. Apixaban are run at 10 μM, 3.16 μM, 1.0 μM, 0.316 μM, 0.1 μM, 0.0316 μM, 0.01 μM, and 0.00316 μM. Plates are read for 30 minutes at 405 nm. Rates are determined in the presence of the controls (no inhibitor) and for the inhibitors. Apixaban are tested in duplicate studies and are compared with the same internal standards. The intraassay and interassay variabilities are 5% and 20%, respectively. All of the enzyme assays are conducted in pH 7.4 buffer at room temperature. All enzymes are purified from human tissues and are obtained from commercially available sources. Individual enzyme and substrate Km are determined in separate experiments and are close to values established in the literature. Steady-state inhibition of enzyme activity is determined by incubating a range of inhibitor concentrations (1 nM to 50 μM, in duplicate) with fixed enzyme (0.1 nM?100 nM) and peptide substrate (200 μM?1000 μM) concentration for up to 30 minutes. The Ki is calculated, assuming competitive inhibition and one-site binding, either from the IC50 or from the extent of inhibition at each inhibitor concentration. |
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Animal Study
[2]
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| Animal Models |
Arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT) and electrically mediated carotid arterial thrombosis (ECAT) rabbit models. |
| Formulation |
Apixaban is dissolved in 10% N,N-dimethylacetamide; 30% 1,2-propanediol; 60% water. |
| Doses |
≤3 mg/kg/h |
| Administration |
Administered via i.v. |
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References |
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[1] Pinto DJ, et al. J Med Chem. 2007, 50(22), 5339-5356.
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[2] Wong PC, et al. J Thromb Haemost. 2008, 6(5), 820-829.
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[3] Zhang D, et al. J Thromb Thrombolysis. 2010, 29(1), 70-80.
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[4] He K, et al. Eur J Drug Metab Pharmacokinet. 2011, 36(3), 129-139.
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