Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Korea.
Heart. 2012 Sep;98(18):1366-72. doi: 10.1136/heartjnl-2012-301892. Epub 2012 Jun 26.
To test the effect of a loss-of-function variation of the cytochrome P450 (CYP) 3A5 on drug-drug interaction between amlodipine and clopidogrel. Amlodipine is a well-known inhibitor of CYP 3A4, an isoenzyme of CYP3A that activates clopidogrel. However, controversy exists regarding whether amlodipine adversely affects clopidogrel response and clinical outcome after percutaneous coronary intervention (PCI). In the presence of CYP3A4 inhibitors such as amlodipine, the genetic variation of CYP3A5, the isoenzyme responsible for the backup CYP3A activity, may play an important role in clopidogrel activation.
Post hoc analysis of a prospectively enrolled cohort.
Patients enrolled in the CROSS-VERIFY cohort from June 2006 to June 2010, with successful genotyping of CYP3A5.
The pharmacodynamic analysis end point was clopidogrel on-treatment platelet reactivity (OPR) and the clinical analysis end point was the composite of cardiac death, non-fatal myocardial infarction, ischaemic stroke and stent thrombosis at 12 months post-PCI.
1258 patients had successful genotyping and were categorised as CYP3A5 non-expressers (749 patients) and expressers (509 patients) according to the CYP3A5 genotype. Amlodipine users showed higher OPR versus non-users only in CYP3A5 non-expressers (249 ± 83 vs 228 ± 84 P2Y12 reaction units, p=0.013). These findings was corroborated by clinical outcomes, in which amlodipine users had a higher incidence of events compared with non-users only in CYP3A5 non-expressers (4.6% vs 0.6%, HR 7.731, CI 2.042 to 29.264, p=0.004).
Treatment with amlodipine is associated with increased clopidogrel OPR and increased risk of thrombotic events after PCI, which is dependent on the CYP3A5 genetic status.
检测细胞色素 P450（CYP）3A5 失活变异对氨氯地平和氯吡格雷药物-药物相互作用的影响。氨氯地平是 CYP3A4 的一种已知抑制剂，CYP3A4 是激活氯吡格雷的同工酶。然而，关于氨氯地平是否会对经皮冠状动脉介入治疗（PCI）后的氯吡格雷反应和临床结局产生不利影响仍存在争议。在存在氨氯地平等 CYP3A4 抑制剂的情况下，负责备用 CYP3A 活性的同工酶 CYP3A5 的遗传变异可能在氯吡格雷的激活中发挥重要作用。
前瞻性入组队列的事后分析。
2006 年 6 月至 2010 年 6 月入组 CROSS-VERIFY 队列并成功进行 CYP3A5 基因分型的患者。
药效学分析终点为氯吡格雷治疗中的血小板反应性（OPR），临床分析终点为 12 个月时的心脏死亡、非致死性心肌梗死、缺血性卒中和支架血栓形成的复合终点。
1258 例患者成功进行了基因分型，根据 CYP3A5 基因型分为 CYP3A5 无表达者（749 例）和表达者（509 例）。与非使用者相比，氨氯地平使用者仅在 CYP3A5 无表达者中显示出更高的 OPR（249±83 与 228±84 P2Y12 反应单位，p=0.013）。这些发现得到了临床结果的证实，与非使用者相比，氨氯地平使用者仅在 CYP3A5 无表达者中发生事件的发生率更高（4.6%与 0.6%，HR 7.731，95%CI 2.042 至 29.264，p=0.004）。
氨氯地平治疗与 PCI 后氯吡格雷 OPR 升高和血栓形成事件风险增加相关，这取决于 CYP3A5 的遗传状态。
