Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Szczecin, Poland.
Department of Cardiology, Pomeranian Medical University, Szczecin, Poland.
Pharmacol Rep. 2021 Apr;73(2):583-593. doi: 10.1007/s43440-020-00197-w. Epub 2020 Dec 3.
Clopidogrel is frequently used as part of optimal dual antiplatelet therapy in high-bleeding risk patients with the acute coronary syndrome. The concentration of the inactive carboxylic acid metabolite of clopidogrel might be useful to evaluate the response to clopidogrel therapy. Therefore, we sought to correlate the inhibition of platelet aggregation with the plasma level of the inactive metabolite of clopidogrel in patients after percutaneous coronary interventions (PCI) and their associations with the most frequently studied genetic polymorphisms. For this purpose, the fast and simple HPLC method for determining the concentration of the inactive metabolite was developed.
The effect of CYP2C19, CYP3A4/5, ABCB1 and PON1 genes on the plasma inactive metabolite concentration of clopidogrel and the platelet aggregation was investigated in 155 patients before and after PCI.
The concentration of the inactive metabolite of clopidogrel was not significantly different in the intermediate metabolizers (IM) of CYP2C19 compared with extensive metabolizers (EM) both before and after PCI, while inhibition of platelet aggregation was found to be significantly better in EM than in IM. The presence of the A allele at position 2677 in the ABCB1 gene was associated with a significantly lower concentration of inactive metabolite of clopidogrel before PCI.
The CYP2C19*2 allele was associated with decreased platelet reactivity during clopidogrel therapy before and after PCI. Simultaneous determination of platelet aggregation and concentration of the inactive clopidogrel metabolite may be useful in clinical practice to find the cause of adverse effects or insufficient treatment effect in patients chronically treated with clopidogrel.
氯吡格雷常用于急性冠脉综合征伴高出血风险患者的最佳双联抗血小板治疗。氯吡格雷无活性羧酸代谢物的浓度可能有助于评估氯吡格雷治疗的反应。因此，我们试图在经皮冠状动脉介入治疗（PCI）后患者中，将血小板聚集抑制与氯吡格雷无活性代谢物的血浆水平相关联，并将其与最常研究的遗传多态性相关联。为此，开发了一种快速简便的 HPLC 方法来测定无活性代谢物的浓度。
在 155 例 PCI 前后的患者中，研究了 CYP2C19、CYP3A4/5、ABCB1 和 PON1 基因对氯吡格雷的血浆无活性代谢物浓度和血小板聚集的影响。
与广泛代谢者（EM）相比，CYP2C19 中间代谢者（IM）的氯吡格雷无活性代谢物浓度在 PCI 前后均无显著差异，而 EM 的血小板聚集抑制作用明显优于 IM。ABCB1 基因 2677 位 A 等位基因的存在与 PCI 前无活性氯吡格雷代谢物浓度显著降低相关。
CYP2C19*2 等位基因与 PCI 前后氯吡格雷治疗期间血小板反应性降低有关。同时测定血小板聚集和无活性氯吡格雷代谢物的浓度可能有助于临床实践中找到长期接受氯吡格雷治疗的患者出现不良反应或治疗效果不佳的原因。
