Department of Laboratory Medicine, Pusan National University Hospital, Busan, Korea.
Br J Clin Pharmacol. 2012 Apr;73(4):629-40. doi: 10.1111/j.1365-2125.2011.04131.x.
Compared with standard dual antiplatelet therapy, adjunctive cilostazol to dual antiplatelet therapy ('triple antiplatelet therapy') has a potential to reduce ischemic event occurrence after percutaneous coronary intervention. The pharmacokinetic and pharmacodynamic effects of clopidogrel have been significantly influenced by the enzyme activity of the ABCB1 C3435T and the CYP2C19 system. • For the pharmacokinetics of cilostazol, genetic polymorphisms of the CYP3A5 and CYP2C19 have been associated with the substantial interindividual variability in healthy volunteers.
Loss-of-function polymorphism of the CYP2C19 gene, but not the ABCB1 C3435T and CYP3A5*3 genes, affects the antiplatelet effect of triple antiplatelet therapy. Most of extensive and intermediate East Asian metabolizers (0 or 1 CYP2C19 loss-of-function allele) show adequate platelet inhibition when treated with triple antiplatelet therapy after percutaneous coronary intervention. However, carriage of 2 CYP2C19 loss-of-function alleles is still associated with the risk of high platelet reactivity (defined by by 5 µM ADP-induced maximal platelet aggregation >46%), which clinical impact needs to be validated in future clinical trials. AIMS Although adjunctive cilostazol to dual antiplatelet therapy can reduce the risks of clinical events after percutaneous coronary intervention (PCI), whether genetic polymorphism can influence the pharmacodynamics of this regimen has not been evaluated.
One hundred and twenty-seven patients treated with PCI and taking triple antiplatelet therapy (≥1 month) were enrolled. Platelet reactivity was assessed by conventional aggregometry and the VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HPR) was defined as 5 µm ADP-induced maximal platelet reactivity (Agg(max) ) >46%. CYP3A53, CYP2C192/*3 and ABCB1 3435C > T were genotyped.
CYP3A5*3 and ABCB1 3435C > T variants did not affect the antiplatelet effect of triple antiplatelet therapy. For non-carriers, one and two carriers of the CYP2C19 loss-of-function (LOF) allele, Agg(max) consecutively increased after the addition of 5 µm[mean (95% confidence intervals): 24.6% (20.8 to 28.5%) vs. 28.7% (25.4 to 32.0%) vs. 32.3% (25.8 to 38.7%), P = 0.062, respectively] and 20 µm ADP [34.2% (29.3 to 39.0%) vs. 41.7% (37.8 to 45.6%) vs. 44.9% (37.9 to 51.9%), P = 0.007, respectively]. Likewise, late platelet reactivity and P2Y12 reaction units proportionally changed according to the number of CYP2C19 LOF alleles. HPRs were observed in 9.2% of subjects: 6.3%, 7.4% and 20.0% with 0, 1 and 2 carriers of CYP2C19 LOF allele(s) (P = 0.099). In multivariate analysis, carriage of two CYP2C19 LOF alleles was a significant predictor for the prevalence of HPR (odds ratio 5.78, 95% CI 1.21, 27.78, P = 0.028).
Among PCI-treated patients, the effect of triple antiplatelet therapy is influenced by the CYP2C19 LOF allele. Its clinical benefit needs to be validated according to the CYP2C19 metabolic phenotype in future clinical trials. [Adjunctive Cilostazol Versus High Maintenance dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism (ACCEL-AMI-2C19), NCT00915733 and Adjunctive Cilostazol Versus High Maintenance-dose Clopidogrel According to Cytochrome 2C19 Polymorphism (ACCEL-2C19), NCT01012193].
与标准双联抗血小板治疗相比，添加西洛他唑的双联抗血小板治疗（“三联抗血小板治疗”）可能会降低经皮冠状动脉介入治疗后的缺血性事件发生率。氯吡格雷的药代动力学和药效学受 ABCB1 C3435T 和 CYP2C19 系统的酶活性的显著影响。
对于西洛他唑的药代动力学，CYP3A5 和 CYP2C19 的遗传多态性与健康志愿者个体间的巨大变异性有关。
CYP2C19 基因的失活突变，而不是 ABCB1 C3435T 和 CYP3A5*3 基因，会影响三联抗血小板治疗的抗血小板作用。大多数广泛和中度东亚代谢者（0 或 1 个 CYP2C19 失活突变等位基因）在经皮冠状动脉介入治疗后接受三联抗血小板治疗时表现出充分的血小板抑制作用。然而，携带 2 个 CYP2C19 失活突变等位基因仍然与高血小板反应性（定义为 5µM ADP 诱导的最大血小板聚集>46%）的风险相关，这一临床影响需要在未来的临床试验中得到验证。
虽然添加西洛他唑的双联抗血小板治疗可以降低经皮冠状动脉介入治疗（PCI）后的临床事件风险，但遗传多态性是否会影响该方案的药效学尚未得到评估。
纳入了 127 名接受 PCI 治疗并接受三联抗血小板治疗（≥1 个月）的患者。通过常规聚集仪和 VerifyNow P2Y12 测定法评估血小板反应性。高治疗时血小板反应性（HPR）定义为 5µM ADP 诱导的最大血小板反应性（Agg(max)）>46%。对 CYP3A53、CYP2C192/*3 和 ABCB1 3435C>T 进行基因分型。
CYP3A5*3 和 ABCB1 3435C>T 变异不影响三联抗血小板治疗的抗血小板作用。对于非携带者，CYP2C19 失活（LOF）等位基因的 1 个和 2 个携带者，加用 5µM ADP 后 Agg(max) 依次增加[平均（95%置信区间）：24.6%（20.8 至 28.5%）比 28.7%（25.4 至 32.0%）比 32.3%（25.8 至 38.7%），P=0.062]，加用 20µM ADP 后[34.2%（29.3 至 39.0%）比 41.7%（37.8 至 45.6%）比 44.9%（37.9 至 51.9%），P=0.007]。同样，根据 CYP2C19 LOF 等位基因的数量，迟发性血小板反应性和 P2Y12 反应单位比例也相应改变。9.2%的患者出现 HPR：0、1 和 2 个 CYP2C19 LOF 等位基因携带者的发生率分别为 6.3%、7.4%和 20.0%（P=0.099）。多变量分析显示，携带 2 个 CYP2C19 LOF 等位基因是 HPR 发生的显著预测因素（比值比 5.78，95%置信区间 1.21 至 27.78，P=0.028）。
在接受 PCI 治疗的患者中，三联抗血小板治疗的效果受 CYP2C19 LOF 等位基因的影响。其临床获益需要根据未来临床试验中的 CYP2C19 代谢表型进行验证。[急性心肌梗死患者中依诺肝素与高维持剂量氯吡格雷对比西洛他唑（ACCEL-AMI-2C19），NCT00915733；依诺肝素与高维持剂量氯吡格雷对比 CYP2C19 多态性（ACCEL-2C19），NCT01012193]。
