QT PRODACT: a multi-site study of in vitro action potential assays on 21 compounds in isolated guinea-pig papillary muscles.
To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (IKr) prolonged action potential duration at 90% repolarization (APD90) in a concentration-dependent manner, those showing Ca2+ current (ICa) inhibition shortened APD30, and those showing Na+ current (INa) inhibition decreased action potential amplitude (APA) and Vmax. Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD90, probably due to their blockade of INa and/or ICa, sometimes leading to a false-negative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with IKr-blocking activity prolonged APD30-90 regardless of their INa- and/or ICa-blocking activities, suggesting that APD30-90 is a useful parameter for evaluating the IKr-blocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD90 and APD30-90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies.
Hayashi
Seiji
S
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Tokyo, Japan. s.hayashi@po.nippon-shinyaku.co.jp
Kii
Yoshihide
Y
Tabo
Mitsuyasu
M
Fukuda
Hitoshi
H
Itoh
Tetsuji
T
Shimosato
Takashi
T
Amano
Hideto
H
Saito
Mamoru
M
Morimoto
Hajime
H
Yamada
Kiyoshi
K
Kanda
Atsuhiro
A
Ishitsuka
Toshimasa
T
Yamazaki
Takanobu
T
Kiuchi
Yoichi
Y
Taniguchi
Shinya
S
Mori
Tatsuya
T
Shimizu
Shigekazu
S
Tsurubuchi
Yuji
Y
Yasuda
Shun-ichi
S
Kitani
Shin-ichi
S
Shimada
Chiaki
C
Kobayashi
Kazuo
K
Komeno
Masaharu
M
Kasai
Chieko
C
Hombo
Toshiyasu
T
Yamamoto
Keiji
K
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001681:Biological Assay; D016208:Databases, Factual; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D004364:Pharmaceutical Preparations
D004364:Pharmaceutical Preparations