QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles.
Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30-60, APD60-90, and APD30-90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30-60, APD60-90, and/or APD30-90; and 8 of the 15 inhibitors prolonged APD30-60, APD60-90, and/or APD30-90 more potently than APD90. The APD30-60, APD60-90, and APD30-90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30-60, APD60-90, or APD30-90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30-60, APD60-90, and APD30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Tokyo, Japan. yoshihide-kii@ds-pharma.co.jp
Yoshihide
Y
Kii
Seiji
S
Hayashi
Mitsuyasu
M
Tabo
Takashi
T
Shimosato
Hitoshi
H
Fukuda
Tetsuji
T
Itoh
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; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016208:Databases, Factual; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers