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.
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Tokyo, Japan. s.hayashi@po.nippon-shinyaku.co.jp
Seiji
S
Hayashi
Yoshihide
Y
Kii
Mitsuyasu
M
Tabo
Hitoshi
H
Fukuda
Tetsuji
T
Itoh
Takashi
T
Shimosato
Hideto
H
Amano
Mamoru
M
Saito
Hajime
H
Morimoto
Kiyoshi
K
Yamada
Atsuhiro
A
Kanda
Toshimasa
T
Ishitsuka
Takanobu
T
Yamazaki
Yoichi
Y
Kiuchi
Shinya
S
Taniguchi
Tatsuya
T
Mori
Shigekazu
S
Shimizu
Yuji
Y
Tsurubuchi
Shun-ichi
S
Yasuda
Shin-ichi
S
Kitani
Chiaki
C
Shimada
Kazuo
K
Kobayashi
Masaharu
M
Komeno
Chieko
C
Kasai
Toshiyasu
T
Hombo
Keiji
K
Yamamoto
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