Wong Pancras C, Crain Earl J, Watson Carol A, Jiang Xiaosui, Hua Ji, Bostwick Jeffrey S, Ogletree Martin L, Schumacher William A, Rehfuss Robert
Discovery Biology, Bristol-Myers Squibb Company, Pennington, New Jersey 08534, USA.
J Cardiovasc Pharmacol. 2007 May;49(5):316-24. doi: 10.1097/FJC.0b013e31803e8772.
Target levels of ex vivo inhibition of platelet aggregation (IPA) induced by adenosine diphosphate (ADP) that produce clinically relevant effects of clopidogrel, a P2Y12 antagonist, are unclear. We examined standard and modified IPA and P2Y12 receptor occupancy as predictors of antithrombotic (% thrombus weight reduction) and bleeding time (BT, fold-increase over control) effects of clopidogrel in rabbit models of carotid artery thrombosis and cuticle bleeding, respectively. Standard and modified IPA with 20 microM ADP were measured in the absence and presence of partial P2Y1 blockade, respectively. Clopidogrel maximally produced standard IPA of 57% +/- 5%, antithrombotic effect of 85% +/- 1%, BT increase of 6.0 +/- 0.4-fold and P2Y12 receptor occupancy of 87% +/- 5%. Surprisingly, a clopidogrel dose that produced a low standard IPA of 17% +/- 4% and P2Y12 receptor occupancy of 39% +/- 5% achieved a significant antithrombotic activity of 55% +/- 2% with a moderate increase in BT of 2.0 +/- 0.1-fold. This underestimation of clopidogrel efficacy by standard IPA was improved by measuring either modified IPA or P2Y12 receptor occupancy. These results suggest that in clopidogrel-treated rabbits, low standard IPA is associated with significant antithrombotic effects. Moreover, modified IPA and P2Y12 receptor occupancy appear to better predict the magnitude of clopidogrel's efficacy compared with standard IPA, which may be a better predictor of BT.
二磷酸腺苷（ADP）诱导的血小板聚集（IPA）的体外抑制目标水平尚不明确，而这一水平会产生P2Y12拮抗剂氯吡格雷的临床相关效应。我们分别在兔颈动脉血栓形成模型和表皮出血模型中，研究了标准和改良IPA以及P2Y12受体占有率，作为氯吡格雷抗血栓形成（血栓重量减少百分比）和出血时间（BT，相对于对照组的增加倍数）效应的预测指标。分别在不存在和存在部分P2Y1阻断的情况下，测量了20微摩尔ADP的标准和改良IPA。氯吡格雷最大可产生57%±5%的标准IPA、85%±1%的抗血栓形成效应、6.0±0.4倍的BT增加以及87%±5%的P2Y12受体占有率。令人惊讶的是，一剂氯吡格雷产生了17%±4%的低标准IPA和39%±5%的P2Y12受体占有率，却实现了55%±2%的显著抗血栓形成活性，同时BT适度增加了2.0±0.1倍。通过测量改良IPA或P2Y12受体占有率，改善了标准IPA对氯吡格雷疗效的低估。这些结果表明，在接受氯吡格雷治疗的兔子中，低标准IPA与显著的抗血栓形成效应相关。此外，与标准IPA相比，改良IPA和P2Y12受体占有率似乎能更好地预测氯吡格雷疗效的大小，而标准IPA可能是BT的更好预测指标。
