title: Antithrombotic and anticoagulant effects of direct factor Xa inhibitor darexaban in rat and rabbit models of venous thrombosis.
abstract: The oral direct factor Xa inhibitor darexaban administered intraduodenally prevented venous thrombus formation in both rats and rabbits with no effect on bleeding. The indirect parenteral Factor Xa inhibitor fondaparinux exerted similar properties, only prolonging bleeding time at extremely high doses. In contrast, the thrombin inhibitor ximelagatran and low-molecular-weight heparin enoxaparin prolonged bleeding time at antithrombotic doses. Studies using human platelets showed darexaban glucuronide, a darexaban metabolite that predominantly determines darexaban antithrombotic effects in vivo, had no effect on platelet activation and aggregation, while heparin and enoxaparin activated platelets. Melagatran, heparin, and enoxaparin all inhibited thrombin-induced platelet aggregation at clinically relevant concentrations. Taken together, these results suggest that thrombin-inhibiting drugs may increase the risk of bleeding, while darexaban may have potential as an orally available antithrombotic agent with a wide therapeutic window.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. seiji.kaku@astellas.com
authors.forename: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Toshio
authors.initials: T
authors.lastname: Uemura
authors.forename: Minori
authors.initials: M
authors.lastname: Saitoh
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Funatsu
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D020719:Glucuronides / Q000494:pharmacology; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D001381:Azepines; D001549:Benzamides; D065427:Factor Xa Inhibitors; D020719:Glucuronides; C570990:darexaban glucuronide; C569750:darexaban