Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

被引：42

作者：

Nozaki, Yumiko ^{[1
]}

Honda, Yayoi ^{[1
]}

Tsujimoto, Shinji ^{[2
]}

Watanabe, Hitoshi ^{[1
]}

Kunimatsu, Takeshi ^{[1
]}

Funabashi, Hitoshi ^{[1
]}

机构：

[1] Dainippon Sumitomo Pharma Co Ltd, Preclin Res Labs, Suita, Osaka 5640053, Japan

[2] Dainippon Sumitomo Pharma Co Ltd, Regenerat & Cellular Med Off, Suita, Osaka 5640053, Japan

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2014年 / 278卷 / 01期

关键词：

Early afterdepolarization (EAD); Field potential duration (FPD); Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs); Multielectrode array (MEA); QT prolongation; Torsade de Pointes (TdP); TORSADE-DE-POINTES; IN-VIVO; VENTRICULAR REPOLARIZATION; GUINEA-PIG; AMIODARONE; SAFETY; MODEL;

D O I：

10.1016/j.taap.2014.04.007

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K+ channel and Ca2+ channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I-Kr and I-Ks blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca2+ channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the IKr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. (C) 2014 Elsevier Inc. All rights reserved.

引用

页码：72 / 77

页数：6

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