Lymperopoulos Anastasios, McCrink Katie A, Brill Ava
Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Dr., HPD (Terry) Bldg/Room 1338, Ft. Lauderdale, FL 33328- 2018, USA.
Curr Drug Metab. 2015;17(1):30-6. doi: 10.2174/1389200217666151105125425.
Carvedilol and metoprolol are two of the most commonly prescribed β-blockers in cardiovascular medicine and primarily used in the treatment of hypertension and heart failure. Cytochrome P450 2D6 (CYP2D6) is the predominant metabolizing enzyme of these two drugs. Since the first description of a CYP2D6 sparteinedebrisoquine polymorphism in the mid-seventies, substantial genetic heterogeneity has been reported in the human CYP2D6 gene, with ~100 different polymorphisms identified to date. Some of these polymorphisms render the enzyme completely inactive while others do not modify its activity. Based on all the identified variants, four metabolizer phenotypes are nowadays used to characterize drug metabolism via CYP2D6 in humans: ultra-rapid metabolizer (UM); extensive metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM) phenotypes. As a consequence of these CYP2D6 metabolizer phenotypes, pharmacokinetics and bioavailability of carvedilol and metoprolol can range from therapeutically ineffective levels (in the UM patients) to excessive (overdose) and potentially toxic concentrations (in PM patients). This, in turn, can result in elevated risks for either treatment failure (in terms of blood pressure reduction of hypertensive patients and of improving survival and cardiovascular function of heart failure patients) or for adverse effects (e.g. hypotension and bradycardia). The present review will discuss the impact of these CYP2D6 genetic polymorphisms on the therapeutic responses of cardiovascular patients treated with either of these two β-blockers. In addition, the potential advantages and disadvantages of implementing CYP2D6 genetic testing in the clinic to guide/personalize therapy with these two drugs will be discussed.
卡维地洛和美托洛尔是心血管医学中最常用的两种β受体阻滞剂，主要用于治疗高血压和心力衰竭。细胞色素P450 2D6（CYP2D6）是这两种药物的主要代谢酶。自20世纪70年代中期首次描述CYP2D6司巴丁/异喹胍多态性以来，已报道人类CYP2D6基因存在大量遗传异质性，迄今已鉴定出约100种不同的多态性。其中一些多态性使该酶完全失活，而其他多态性则不改变其活性。基于所有已鉴定的变体，目前使用四种代谢者表型来表征人类通过CYP2D6进行的药物代谢：超快代谢者（UM）；广泛代谢者（EM）；中间代谢者（IM）；以及慢代谢者（PM）表型。由于这些CYP2D6代谢者表型，卡维地洛和美托洛尔的药代动力学和生物利用度范围可以从治疗无效水平（在UM患者中）到过量（过量用药）和潜在的中毒浓度（在PM患者中）。这反过来可能导致治疗失败（就高血压患者的血压降低以及改善心力衰竭患者的生存率和心血管功能而言）或不良反应（如低血压和心动过缓）的风险增加。本综述将讨论这些CYP2D6基因多态性对接受这两种β受体阻滞剂之一治疗的心血管患者治疗反应的影响。此外，还将讨论在临床中进行CYP2D6基因检测以指导/个性化这两种药物治疗的潜在优缺点。
