Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor
Darexaban (YM150) is an oral factor Xa inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This study was conducted to investigate the biochemical and pharmacological profiles of darexaban and its active metabolite darexaban glucuronide (YM-222714), which predomina...
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| Veröffentlicht in: | European journal of pharmacology 2011-12, Vol.673 (1), p.49-55 |
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| creator | Iwatsuki, Yoshiyuki Sato, Takayuki Moritani, Yumiko Shigenaga, Takeshi Suzuki, Mami Kawasaki, Tomihisa Funatsu, Toshiyuki Kaku, Seiji |
| description | Darexaban (YM150) is an oral factor Xa inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This study was conducted to investigate the biochemical and pharmacological profiles of darexaban and its active metabolite darexaban glucuronide (YM-222714), which predominantly determines the antithrombotic effect after oral administration of darexaban.
In vitro activity was evaluated by enzyme and coagulation assays, and a prothrombin activation assay using reconstituted prothrombinase or whole blood clot.
In vivo effects were examined in venous thrombosis, arterio–venous (A–V) shunt thrombosis, and bleeding models in rats. Both darexaban and darexaban glucuronide competitively and selectively inhibited human factor Xa with
Ki values of 0.031 and 0.020
μM, respectively. They showed anticoagulant activity in human plasma, with doubling concentrations of darexaban and darexaban glucuronide for prothrombin time of 1.2 and 0.95
μM, respectively. Anticoagulant activity was independent of antithrombin. Darexaban and darexaban glucuronide inhibited the prothrombin activation induced by prothrombinase complex or whole blood clot with similar potency to free factor Xa. In contrast, prothrombinase- and clot-induced prothrombin activation were resistant to inhibition by enoxaparin. In venous and A–V shunt thrombosis models in rats, darexaban strongly suppressed thrombus formation without affecting bleeding time, with ID
50 values of 0.97 and 16.7
mg/kg, respectively. Warfarin also suppressed thrombus formation in these models, but caused a marked prolongation of bleeding time at antithrombotic dose. In conclusion, darexaban is a selective and direct factor Xa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases. |
| doi_str_mv | 10.1016/j.ejphar.2011.10.009 |
| format | Article |
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In vitro activity was evaluated by enzyme and coagulation assays, and a prothrombin activation assay using reconstituted prothrombinase or whole blood clot.
In vivo effects were examined in venous thrombosis, arterio–venous (A–V) shunt thrombosis, and bleeding models in rats. Both darexaban and darexaban glucuronide competitively and selectively inhibited human factor Xa with
Ki values of 0.031 and 0.020
μM, respectively. They showed anticoagulant activity in human plasma, with doubling concentrations of darexaban and darexaban glucuronide for prothrombin time of 1.2 and 0.95
μM, respectively. Anticoagulant activity was independent of antithrombin. Darexaban and darexaban glucuronide inhibited the prothrombin activation induced by prothrombinase complex or whole blood clot with similar potency to free factor Xa. In contrast, prothrombinase- and clot-induced prothrombin activation were resistant to inhibition by enoxaparin. In venous and A–V shunt thrombosis models in rats, darexaban strongly suppressed thrombus formation without affecting bleeding time, with ID
50 values of 0.97 and 16.7
mg/kg, respectively. Warfarin also suppressed thrombus formation in these models, but caused a marked prolongation of bleeding time at antithrombotic dose. In conclusion, darexaban is a selective and direct factor Xa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2011.10.009</identifier><identifier>PMID: 22040919</identifier><identifier>CODEN: EJPHAZ</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Administration, Oral ; Animals ; anticoagulant activity ; anticoagulants ; Anticoagulants - administration & dosage ; Anticoagulants - metabolism ; Anticoagulants - pharmacology ; Antithrombin ; Azepines - administration & dosage ; Azepines - metabolism ; Azepines - pharmacology ; Benzamides - administration & dosage ; Benzamides - metabolism ; Benzamides - pharmacology ; Biological and medical sciences ; Bleeding ; Bleeding Time ; blood ; coagulation ; disease control ; Disease Models, Animal ; Dogs ; Dose-Response Relationship, Drug ; enoxaparin ; Enoxaparin - pharmacology ; Factor Xa inhibitor ; Factor Xa Inhibitors ; Glucuronidation ; Glucuronides - administration & dosage ; Glucuronides - pharmacology ; hemorrhage ; Humans ; Macaca fascicularis ; Male ; Medical sciences ; metabolites ; Mice ; Mice, Inbred ICR ; oral administration ; Oral anticoagulant ; Pharmacology. Drug treatments ; prothrombin ; Prothrombin Time ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Thrombosis ; Thrombosis - drug therapy ; Thrombosis - physiopathology ; Venous Thrombosis - drug therapy ; Venous Thrombosis - physiopathology ; warfarin ; Warfarin - pharmacology</subject><ispartof>European journal of pharmacology, 2011-12, Vol.673 (1), p.49-55</ispartof><rights>2011 Elsevier B.V.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-22bde21d5e4cec0322f6ceb351b19d6b40f1325411452cdb2a8532f6fe29eb863</citedby><cites>FETCH-LOGICAL-c481t-22bde21d5e4cec0322f6ceb351b19d6b40f1325411452cdb2a8532f6fe29eb863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014299911012398$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24797432$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22040919$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iwatsuki, Yoshiyuki</creatorcontrib><creatorcontrib>Sato, Takayuki</creatorcontrib><creatorcontrib>Moritani, Yumiko</creatorcontrib><creatorcontrib>Shigenaga, Takeshi</creatorcontrib><creatorcontrib>Suzuki, Mami</creatorcontrib><creatorcontrib>Kawasaki, Tomihisa</creatorcontrib><creatorcontrib>Funatsu, Toshiyuki</creatorcontrib><creatorcontrib>Kaku, Seiji</creatorcontrib><title>Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Darexaban (YM150) is an oral factor Xa inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This study was conducted to investigate the biochemical and pharmacological profiles of darexaban and its active metabolite darexaban glucuronide (YM-222714), which predominantly determines the antithrombotic effect after oral administration of darexaban.
In vitro activity was evaluated by enzyme and coagulation assays, and a prothrombin activation assay using reconstituted prothrombinase or whole blood clot.
In vivo effects were examined in venous thrombosis, arterio–venous (A–V) shunt thrombosis, and bleeding models in rats. Both darexaban and darexaban glucuronide competitively and selectively inhibited human factor Xa with
Ki values of 0.031 and 0.020
μM, respectively. They showed anticoagulant activity in human plasma, with doubling concentrations of darexaban and darexaban glucuronide for prothrombin time of 1.2 and 0.95
μM, respectively. Anticoagulant activity was independent of antithrombin. Darexaban and darexaban glucuronide inhibited the prothrombin activation induced by prothrombinase complex or whole blood clot with similar potency to free factor Xa. In contrast, prothrombinase- and clot-induced prothrombin activation were resistant to inhibition by enoxaparin. In venous and A–V shunt thrombosis models in rats, darexaban strongly suppressed thrombus formation without affecting bleeding time, with ID
50 values of 0.97 and 16.7
mg/kg, respectively. Warfarin also suppressed thrombus formation in these models, but caused a marked prolongation of bleeding time at antithrombotic dose. In conclusion, darexaban is a selective and direct factor Xa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>anticoagulant activity</subject><subject>anticoagulants</subject><subject>Anticoagulants - administration & dosage</subject><subject>Anticoagulants - metabolism</subject><subject>Anticoagulants - pharmacology</subject><subject>Antithrombin</subject><subject>Azepines - administration & dosage</subject><subject>Azepines - metabolism</subject><subject>Azepines - pharmacology</subject><subject>Benzamides - administration & dosage</subject><subject>Benzamides - metabolism</subject><subject>Benzamides - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bleeding</subject><subject>Bleeding Time</subject><subject>blood</subject><subject>coagulation</subject><subject>disease control</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>enoxaparin</subject><subject>Enoxaparin - pharmacology</subject><subject>Factor Xa inhibitor</subject><subject>Factor Xa Inhibitors</subject><subject>Glucuronidation</subject><subject>Glucuronides - administration & dosage</subject><subject>Glucuronides - pharmacology</subject><subject>hemorrhage</subject><subject>Humans</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>metabolites</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>oral administration</subject><subject>Oral anticoagulant</subject><subject>Pharmacology. Drug treatments</subject><subject>prothrombin</subject><subject>Prothrombin Time</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Thrombosis</subject><subject>Thrombosis - drug therapy</subject><subject>Thrombosis - physiopathology</subject><subject>Venous Thrombosis - drug therapy</subject><subject>Venous Thrombosis - physiopathology</subject><subject>warfarin</subject><subject>Warfarin - pharmacology</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0EotvCP0CQC-qFLB7HycaXSlBBQarEASr1Zvlj3PUqiRd7F7X_nlmylBsny-NnZl49ZuwV8CVw6N5vlrjZrk1eCg5ApSXn6glbQL9SNV-BeMoWnIOshVLqhJ2WsuGct0q0z9mJEFxyBWrBbj_G5NY4RmeGyky-OowcjUtDuvtT2-YU4oBVCpU3Ge-NNdM7IquU6dXHjG5XBeN2KVe3porTOtpIlxfsWTBDwZfH84zdfP704_JLff3t6uvlh-vayR52tRDWowDfonToeCNE6BzapgULyndW8gCNaCWAbIXzVpi-bYgJKBTavmvO2Pk8l4L-3GPZ6TEWh8NgJkz7ohXvgNp5T6ScSZdTKRmD3uY4mvyggeuDUr3Rs1J9UHqoklJqe31csLcj-semvw4JeHsETCFjIZvJxfKPkyu1ko0g7s3MBZO0ucvE3HynTS39i6SUkoiLmUAS9iti1sVFnBzOmrVP8f9ZfwPOa59I</recordid><startdate>20111230</startdate><enddate>20111230</enddate><creator>Iwatsuki, Yoshiyuki</creator><creator>Sato, Takayuki</creator><creator>Moritani, Yumiko</creator><creator>Shigenaga, Takeshi</creator><creator>Suzuki, Mami</creator><creator>Kawasaki, Tomihisa</creator><creator>Funatsu, Toshiyuki</creator><creator>Kaku, Seiji</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20111230</creationdate><title>Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor</title><author>Iwatsuki, Yoshiyuki ; Sato, Takayuki ; Moritani, Yumiko ; Shigenaga, Takeshi ; Suzuki, Mami ; Kawasaki, Tomihisa ; Funatsu, Toshiyuki ; Kaku, Seiji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-22bde21d5e4cec0322f6ceb351b19d6b40f1325411452cdb2a8532f6fe29eb863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>anticoagulant activity</topic><topic>anticoagulants</topic><topic>Anticoagulants - administration & dosage</topic><topic>Anticoagulants - metabolism</topic><topic>Anticoagulants - pharmacology</topic><topic>Antithrombin</topic><topic>Azepines - administration & dosage</topic><topic>Azepines - metabolism</topic><topic>Azepines - pharmacology</topic><topic>Benzamides - administration & dosage</topic><topic>Benzamides - metabolism</topic><topic>Benzamides - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bleeding</topic><topic>Bleeding Time</topic><topic>blood</topic><topic>coagulation</topic><topic>disease control</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>enoxaparin</topic><topic>Enoxaparin - pharmacology</topic><topic>Factor Xa inhibitor</topic><topic>Factor Xa Inhibitors</topic><topic>Glucuronidation</topic><topic>Glucuronides - administration & dosage</topic><topic>Glucuronides - pharmacology</topic><topic>hemorrhage</topic><topic>Humans</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>metabolites</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>oral administration</topic><topic>Oral anticoagulant</topic><topic>Pharmacology. Drug treatments</topic><topic>prothrombin</topic><topic>Prothrombin Time</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Thrombosis</topic><topic>Thrombosis - drug therapy</topic><topic>Thrombosis - physiopathology</topic><topic>Venous Thrombosis - drug therapy</topic><topic>Venous Thrombosis - physiopathology</topic><topic>warfarin</topic><topic>Warfarin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iwatsuki, Yoshiyuki</creatorcontrib><creatorcontrib>Sato, Takayuki</creatorcontrib><creatorcontrib>Moritani, Yumiko</creatorcontrib><creatorcontrib>Shigenaga, Takeshi</creatorcontrib><creatorcontrib>Suzuki, Mami</creatorcontrib><creatorcontrib>Kawasaki, Tomihisa</creatorcontrib><creatorcontrib>Funatsu, Toshiyuki</creatorcontrib><creatorcontrib>Kaku, Seiji</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iwatsuki, Yoshiyuki</au><au>Sato, Takayuki</au><au>Moritani, Yumiko</au><au>Shigenaga, Takeshi</au><au>Suzuki, Mami</au><au>Kawasaki, Tomihisa</au><au>Funatsu, Toshiyuki</au><au>Kaku, Seiji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2011-12-30</date><risdate>2011</risdate><volume>673</volume><issue>1</issue><spage>49</spage><epage>55</epage><pages>49-55</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>Darexaban (YM150) is an oral factor Xa inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This study was conducted to investigate the biochemical and pharmacological profiles of darexaban and its active metabolite darexaban glucuronide (YM-222714), which predominantly determines the antithrombotic effect after oral administration of darexaban.
In vitro activity was evaluated by enzyme and coagulation assays, and a prothrombin activation assay using reconstituted prothrombinase or whole blood clot.
In vivo effects were examined in venous thrombosis, arterio–venous (A–V) shunt thrombosis, and bleeding models in rats. Both darexaban and darexaban glucuronide competitively and selectively inhibited human factor Xa with
Ki values of 0.031 and 0.020
μM, respectively. They showed anticoagulant activity in human plasma, with doubling concentrations of darexaban and darexaban glucuronide for prothrombin time of 1.2 and 0.95
μM, respectively. Anticoagulant activity was independent of antithrombin. Darexaban and darexaban glucuronide inhibited the prothrombin activation induced by prothrombinase complex or whole blood clot with similar potency to free factor Xa. In contrast, prothrombinase- and clot-induced prothrombin activation were resistant to inhibition by enoxaparin. In venous and A–V shunt thrombosis models in rats, darexaban strongly suppressed thrombus formation without affecting bleeding time, with ID
50 values of 0.97 and 16.7
mg/kg, respectively. Warfarin also suppressed thrombus formation in these models, but caused a marked prolongation of bleeding time at antithrombotic dose. In conclusion, darexaban is a selective and direct factor Xa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>22040919</pmid><doi>10.1016/j.ejphar.2011.10.009</doi><tpages>7</tpages></addata></record> |
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| ispartof | European journal of pharmacology, 2011-12, Vol.673 (1), p.49-55 |
| issn | 0014-2999 1879-0712 |
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| subjects | Administration, Oral Animals anticoagulant activity anticoagulants Anticoagulants - administration & dosage Anticoagulants - metabolism Anticoagulants - pharmacology Antithrombin Azepines - administration & dosage Azepines - metabolism Azepines - pharmacology Benzamides - administration & dosage Benzamides - metabolism Benzamides - pharmacology Biological and medical sciences Bleeding Bleeding Time blood coagulation disease control Disease Models, Animal Dogs Dose-Response Relationship, Drug enoxaparin Enoxaparin - pharmacology Factor Xa inhibitor Factor Xa Inhibitors Glucuronidation Glucuronides - administration & dosage Glucuronides - pharmacology hemorrhage Humans Macaca fascicularis Male Medical sciences metabolites Mice Mice, Inbred ICR oral administration Oral anticoagulant Pharmacology. Drug treatments prothrombin Prothrombin Time Rabbits Rats Rats, Sprague-Dawley Thrombosis Thrombosis - drug therapy Thrombosis - physiopathology Venous Thrombosis - drug therapy Venous Thrombosis - physiopathology warfarin Warfarin - pharmacology |
| title | Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor |
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