Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs.
Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80 mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20 nM, and arrhythmias at 200-400 nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.
Nilsson
M F
MF
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, Sweden. Mats.Nilsson@farmbio.uu.se
Danielsson
C
C
Sköld
A-C
AC
Johansson
A
A
Blomgren
B
B
Wilson
J
J
Khan
K M
KM
Bengtsson
E
E
Kultima
K
K
Webster
W S
WS
Danielsson
B R
BR
D000014:Abnormalities, Drug-Induced; D000818:Animals; D016589:Astemizole / Q000633:toxicity*; D017332:Cetirizine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects / Q000503:physiopathology; D047108:Embryonic Development / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D039563:Histamine H1 Antagonists, Non-Sedating / Q000633:toxicity*; D000860:Hypoxia / Q000139:chemically induced / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D018811:Maternal Exposure; D009593:Nitroimidazoles; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000145:classification / Q000633:toxicity*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D039563:Histamine H1 Antagonists, Non-Sedating; D009593:Nitroimidazoles; D024661:Potassium Channels, Inwardly Rectifying; D013723:Teratogens; C033815:pimonidazole; D016589:Astemizole; D017332:Cetirizine