封锁HERG心脏K +电流的抗真菌药物咪康唑。

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菊池K, Nagatomo T,安倍H,川上K,达夫HJ, Makielski JC, 1月CT,中岛美嘉Y

封锁HERG心脏K +电流的抗真菌药物咪康唑。

Br J杂志。2005年3月,144 (6):840 - 8。

PubMed ID

15778703 (在PubMed

]

文摘

1。咪康唑,咪唑抗真菌剂,与获得长QT综合症和室性心律失常。咪康唑血浆浓度的增加QT-prolonging药物通过抑制肝细胞色素P450代谢途径,但是否有直接作用于心脏离子通道尚未阐明。2。这些临床表现确定机制,我们调查的影响人类ether-a-go-go-related咪康唑基因(HERG) K +通道。3所示。HERG通道是不同的表达(HEK293) 293年人类胚胎肾细胞全细胞电流记录使用膜片箝技术(23摄氏度)。4。咪康唑抑制HERG尾电流峰值浓度的方式(0.4 -40 microM)的IC50 2.1 microM (n = 3 - 5细胞在每一集中,希尔系数1.2)。HERG块没有频率相关。它要求通道激活,发生迅速,非常缓慢的分离性能。 5. The activation curve was shifted in a negative direction (V(1/2): -9.5+/-2.3 mV in controls and -15.3+/-2.4 mV after 4 microM miconazole, P<0.05, n=6). Miconazole did not change other channel kinetics (activation, deactivation, onset of inactivation, recovery from inactivation, steady-state inactivation). 6. The S6 domain mutation, F656C, abolished the inhibitory action of miconazole on HERG current indicating that miconazole preferentially binds to an aromatic amino-acid residue within the pore-S6 region. 7. Our findings indicate that miconazole causes HERG channel block by binding to a common drug receptor, and this involves preferential binding to activated channels. Thus, miconazole prolongs the QT interval by direct inhibition of HERG channels.

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药物靶点

药物	目标	类	生物	药理作用	行动
咪康唑	电压门控钾通道(蛋白质组)	蛋白质组		未知的	抑制剂	细节