A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats
A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats
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DOI：
10.1111/bph.12108
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发表时间：
2013-05-01
影响因子：
7.3
通讯作者：
Tomizawa, A.
中科院分区：
文献类型：
--
作者：
Sugidachi, A.;Ohno, K.;Tomizawa, A.
背景和目的普拉格雷是第三代噻吩并吡啶前药，替格瑞洛是非竞争性P2 Y12受体拮抗剂。在他们的3期研究中，相对于氯吡格雷治疗，两种药物均降低了缺血事件的发生率。实验方法在大鼠中比较普拉格雷与替格瑞洛的抗血小板作用的药效学特征。关键结果普拉格雷的活性代谢产物在体外对血小板聚集的作用不如替格瑞洛及其活性代谢产物。相比之下，普拉格雷是一种比替格瑞洛更有效的体外血小板聚集抗血小板药物：其峰值时ADP 20 mol中心点L1的ED 50值分别为1.9和8.0 mg中心点kg-1。普拉格雷对血小板聚集的抑制作用在给药后可维持长达24小时，但替格瑞洛的作用持续时间明显较短。普拉格雷和替格瑞洛显著抑制血栓形成，ED 50值分别为1.8和7.7mg中心点kg-1。两种药物还延长了出血时间（ED 200值分别为3.0和13 mg中心点kg 1），表明在同等水平的血小板聚集抑制作用下，两种药物显示出相当的抗血栓形成活性，出血风险相似。在普拉格雷和替格瑞洛治疗的大鼠中，血小板输注显著增加血小板数量。在普拉格雷治疗组中，血小板输注导致出血时间显著缩短，而在替格瑞洛治疗组中，血小板输注在所采用的实验条件下对出血时间没有影响。结论和意义普拉格雷和替格瑞洛在其药理学特征方面存在一些差异，这些差异可能反映了其不同的可逆性和/或药代动力学特征。
Background and Purpose Prasugrel is a third-generation thienopyridine prodrug and ticagrelor is a non-competitive P2Y12 receptor antagonist. In their phase 3 studies, both agents reduced rates of ischemic events relative to treatment with clopidogrel. Experimental Approach The pharmacodynamic profile of anti-platelet effects of prasugrel was compared with that of ticagrelor in rats. Key Results The active metabolite of prasugrel was less potent than ticagrelor and its active metabolite on platelet aggregation in vitro. In contrast, prasugrel was a more potent antiplatelet agent than ticagrelor on ex vivo platelet aggregation: their ED50 values at peak for ADP 20mol center dot L1 were 1.9 and 8.0mg center dot kg1, respectively. Prasugrel's inhibition of platelet aggregation was maintained for up to 24h after administration, but ticagrelor's duration of action was substantially shorter. Prasugrel and ticagrelor significantly inhibited thrombus formation with ED50 values of 1.8 and 7.7mg center dot kg1, respectively. Both agents also prolonged bleeding times (ED200 values of 3.0 and 13mg center dot kg1 respectively) suggesting that at equivalent levels of inhibition of platelet aggregation, the agents would show comparable antithrombotic activity with similar bleeding risk. Platelet transfusion significantly increased blood platelet numbers similarly in prasugrel- and ticagrelor-treated rats. In the prasugrel-treated group, platelet transfusion caused significant shortening of bleeding time, while in the ticagrelor-treated group, platelet transfusion showed no influence on bleeding time under the experimental conditions employed. Conclusions and Implications Prasugrel and ticagrelor showed several differences in their pharmacological profiles and these disparities may reflect their differing reversibility and/or pharmacokinetic profiles.