Repeat oral dosing of prasugrel, a novel P2Y12 receptor inhibitor, results in cumulative and potent antiplatelet and antithrombotic activity in several animal species

• Published in: European journal of pharmacology 2008-01, Vol.579 (1-3), p.276-282
• Main Authors: NIITSU, Yoichi, SUGIDACHI, Atsuhiro, OGAWA, Taketoshi, JAKUBOWSKI, Joseph A, HASHIMOTO, Masami, ISOBE, Takashi, OTSUGURO, Ken-Ichi, ASAI, Fumitoshi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; In Vitro Techniques; Macaca fascicularis; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - pharmacology; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacology; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Rabbits; Rats; Rats, Sprague-Dawley; Species Specificity; Thiophenes - administration & dosage; Thiophenes - pharmacology; Thrombosis - drug therapy; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.10.005

Antiplatelet and antithrombotic activity of multiple oral dosing of prasugrel were evaluated in several animal species. Prasugrel's active metabolite concentration-relatedly inhibited in vitro ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets. Oral administration of prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of prasugrel and clopidogrel were further examined in rats. Multiple oral dosing of prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to clopidogrel (3-30 mg/kg/day) and ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial thrombosis, prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of prasugrel was about 10 and 300 times more potent than clopidogrel and ticlopidine, respectively. Overall these results show that in several species multiple oral administration of prasugrel results in more potent inhibition of platelet aggregation and thrombus formation than clopidogrel and ticlopidine, and that these effects are mediated by inhibition of platelet ADP receptors.