Carvedilol: a new candidate for reversal of MDR1/P-glycoprotein-mediated multidrug resistance
Carvedilol: a new candidate for reversal of MDR1/P-glycoprotein-mediated multidrug resistance
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DOI：
10.1097/00001813-200404000-00001
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发表时间：
2004-04
影响因子：
2.3
通讯作者：
K. Takara;T. Sakaeda;K. Okumura
中科院分区：
文献类型：
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作者：
K. Takara;T. Sakaeda;K. Okumura
卡维地洛[1-[咔唑基-（4）-氧]-3-[（2-甲氧基苯氧基乙基）氨基]-2-丙醇]是1983年设计并开发的一种具有血管舒张活性的β-肾上腺素能受体拮抗剂，用于有效和安全地治疗高血压和冠状动脉疾病。卡维地洛属于第三代β-肾上腺素受体拮抗剂，对1-肾上腺素受体而非2-肾上腺素受体具有选择性。卡维地洛也是1-受体阻滞剂，对1-受体的选择性比对1-受体的选择性高2- 3倍。这种程度的1-阻断是卡维地洛的中度血管扩张特性的原因，不同于其他β-肾上腺素受体拮抗剂。此外，卡维地洛是一种有效的抗氧化剂，活性比维生素E高10倍。在人血浆中发现的一些卡维地洛代谢物也表现出比卡维地洛和其他抗氧化剂高约50至100倍的抗氧化活性。卡维地洛的这些独特性质，即肾上腺素能（1，2和1）阻滞和抗氧化活性，可能在预防左心室功能障碍和慢性心力衰竭的进行性恶化方面很重要。近年来，卡维地洛在体外被证实能逆转肿瘤细胞对抗癌药物的多药耐药（multidrug resistance，MDR），其逆转作用与维拉帕米相当，后者已首次用于逆转MDR的临床试验。本文介绍了卡维地洛的逆转活性和有效性，以及卡维地洛的药理学和药代动力学特性的概述。
In 1983, carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-propanol] was designed and developed as a -adrenoceptor antagonist with vasodilating activity for efficacious and safe treatment of hypertension and coronary artery disease. Carvedilol belongs to the ‘third generation’ of -adrenoceptor antagonists and shows selectivity for the 1- rather than 2-adrenoceptor. Carvedilol is also an 1-blocking agents, with around 2- to 3-fold more selectivity for 1- than 1-adrenoceptors. This degree of 1-blockade is responsible for the moderate vasodilator properties of carvedilol, being different from other -adrenoceptor antagonists. In addition, carvedilol is a potent antioxidant, with a 10-fold greater activity than vitamin E. Some carvedilol metabolites found in human plasma also exhibit antioxidative activity approximately 50- to 100-fold greater than carvedilol and other antioxidants. These unique properties of carvedilol, i.e. adrenergic (1, 2 and 1) blockade and antioxidative activity, may be important in preventing progressive deterioration of left ventricular dysfunction and chronic heart failure. Recently, carvedilol has been demonstrated to reverse multidrug resistance (MDR) to anticancer drugs in tumor cells in vitro and its reversal effects were comparable with verapamil, which has been used in the first clinical trial for the reversal of MDR. This review introduces the reversal activity and usefulness against MDR, as well as an overview of the pharmacological and pharmacokinetic properties, of carvedilol.