title: Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation.
abstract: 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 Ca(2+) 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 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration. IKr and IKs blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca(2+) 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.
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053, Japan. Electronic address: yumiko-nozaki@ds-pharma.co.jp.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053, Japan. Electronic address: yayoi-honda@ds-pharma.co.jp.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Regenerative & Cellular Medicine Office, Dainippon Sumitomo Pharma. Co., Ltd., Chuo-ku, Tokyo 104-0031, Japan. Electronic address: shinji-tsujimoto@ds-pharma.co.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsujimoto
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053, Japan. Electronic address: hitoshi-1-watanabe@ds-pharma.co.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053, Japan. Electronic address: takeshi-kunimatsu@ds-pharma.co.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kunimatsu
authors.affiliation: Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053, Japan. Electronic address: hitoshi-funabashi@ds-pharma.co.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Funabashi
mesh_terms: D000200:Action Potentials; D002121:Calcium Channel Blockers / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000633:toxicity*; D018570:Risk Assessment; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers
keywords: 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)