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使用氨氯地平,而非 P-糖蛋白抑制型钙通道阻滞剂与氯吡格雷反应不佳相关。

The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response.

机构信息

Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands.

出版信息

Thromb Haemost. 2010 May;103(5):920-5. doi: 10.1160/TH09-08-0516. Epub 2010 Mar 29.

Abstract

Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

摘要

氯吡格雷是一种前体药物,必须在体内由细胞色素 (CYP)P450 同工酶转化为其活性代谢物。由于钙通道阻滞剂 (CCB) 是 CYP3A4 的抑制剂,因此这些药物的同时使用可能在氯吡格雷反应的个体间广泛差异中发挥作用。然而,一些 CCB 也对药物转运蛋白 P-糖蛋白 (Pgp) 具有强烈的抑制作用,Pgp 介导氯吡格雷的肠道吸收。本研究旨在评估同时使用具有抑制 Pgp 作用和不具有抑制 Pgp 作用的 CCB 对接受双重抗血小板治疗并行择期经皮冠状动脉介入治疗 (PCI) 的患者氯吡格雷血小板反应的影响。在总共 623 例接受择期 PCI 治疗的连续患者中,使用氯吡格雷和阿司匹林,通过光透射聚集法评估对 5 和 20 μM 二磷酸腺苷 (ADP) 的血小板反应性和氯吡格雷反应不良(定义为 20 μM ADP 诱导的血小板聚集 > 70%)。共有 222 例患者(35.6%)正在接受 CCB 治疗,其中 98 例使用 Pgp 抑制性 CCB(维拉帕米、硝苯地平、地尔硫卓、巴尼地平),124 例患者使用非 Pgp 抑制性 CCB 氨氯地平。与 CCB 非使用者相比,使用 Pgp 抑制性 CCB 和氨氯地平的患者 ADP 诱导的氯吡格雷血小板反应性的调整平均水平均显著升高(均 p<0.05)。然而,只有使用氨氯地平与氯吡格雷反应不良的风险增加 2.3 倍显著相关。本研究表明,同时使用 Pgp 抑制性 CCB 和氨氯地平会增加氯吡格雷的血小板反应性。只有氨氯地平与氯吡格雷反应不良相关。与 P-糖蛋白抑制性 CCB 相比,氯吡格雷和氨氯地平之间的药物相互作用可能更具临床相关性。

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