Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study
Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study
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DOI：
10.1007/s00228-020-02832-0
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发表时间：
2020-01-15
影响因子：
2.9
通讯作者：
Oie, Erik
中科院分区：
文献类型：
--
作者：
Anstensrud, Anne Kristine;Molden, Espen;Oie, Erik
目的β 1肾上腺素能受体阻滞剂美托洛尔主要由多态性酶细胞色素P450 2D 6（CYP 2D 6）代谢，该酶具有明显的遗传异质性。本研究的目的是探讨CYP 2D 6代谢对心肌梗死（MI）患者美托洛尔临床疗效和耐受性的影响。方法我们纳入了136例接受美托洛尔治疗的MI患者，并建议全科医生（GP）在可能的情况下在2个月内将美托洛尔剂量增加至200 mg/d。在随访时，测量了剂量上调后的美托洛尔剂量、美托洛尔稳态血浆谷浓度、血流动力学参数、潜在的美托洛尔诱导的药物不良反应和GP访视次数。随访结束后进行CYP 2D 6基因分型，包括功能降低的变异等位基因CYP 2D 6 *9、CYP 2D 6 *10和CYP 2D 6 *41。结果按CYP 2D 6基因型划分，美托洛尔快代谢型（EM）占30%，中代谢型（IM）占55%，慢代谢型（PM）占13%; IM组（2倍）和PM组（6.2倍）剂量调整后的美托洛尔谷浓度显著高于EM组（p < 0.001）。PM组中只有35%的患者达到了主要终点，即在运动期间达到至少85%的预期最大心率（HR），而EM组为78%（p < 0.01），PM组运动时观察到的最大HR显著低于EM组（129 +/- 5 vs. 142 +/- 2 bpm，p < 0.007）。相比之下，美托洛尔维持剂量、血压、运动能力、GP访视次数以及自我报告的潜在美托洛尔相关药物不良反应的频率和严重程度在两组之间无显著差异。结论使用综合CYP 2D 6基因分型组，本研究表明CYP 2D 6 PM与EM相比，剂量调整后的血浆美托洛尔谷浓度增加> 6倍，运动期间达到的最大HR平行增加较低，但基因型与自我报告的药物不良反应的频率或严重程度无关。这可能表明，在自然环境中，CYP 2D 6 PM可能受益于每剂量增加的血浆浓度。
Purpose The beta-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI). Methods We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200 mg/day within 2 months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up. Results According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p < 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p < 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 +/- 5 vs. 142 +/- 2 bpm, p < 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups. Conclusion Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.