Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
2010 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 29, no 2, 156-163 p.Article in journal (Refereed) Published
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 (80mg/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 20nM, and arrhythmias at 200-400nM. 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.
Place, publisher, year, edition, pages
Elsevier , 2010. Vol. 29, no 2, 156-163 p.
Astemizole, hERG channel, IKr, Teratogenicity, Hypoxia, Embryonic cardiac adverse effects, Embryotoxicity, Toxicology
Pharmaceutical Sciences Computer Vision and Robotics (Autonomous Systems)
Research subject Toxicology; Computerized Image Processing
IdentifiersURN: urn:nbn:se:uu:diva-118335DOI: 10.1016/j.reprotox.2010.01.014ISI: 000276326900004PubMedID: 20144703OAI: oai:DiVA.org:uu-118335DiVA: diva2:299024