Teratogenicity of the I(Kr)-blocker cisapride: relation to embryonic cardiac arrhythmia.
Cisapride and mosapride are structurally and pharmacologically related prokinetic agents. In contrast to mosapride, cisapride causes embryonic lethality in teratology studies, and has been related to fatal cardiac arrhythmia in the adult. The arrhythmogenic potential of cisapride is linked to its potential to inhibit a specific ion channel (I(Kr)) as a side effect. Mosapride lacks I(Kr)-blocking properties. The aims of this study were (1) to compare the effects of cisapride and mosapride on embryonic heart rhythm in vitro and (2) to investigate if cisapride in vivo, has potential to induce hypoxia-related teratogenic effects as has been shown for selective I(Kr)-blockers. Cisapride induced severe embryonic bradycardia (approximately 60% decrease), and arrhythmia in 94% of the cultured rat embryos at 1000 ng/ml. Mosapride did not induce any bradycardia or arrhythmia up to 2000 ng/ml. In vivo, single dose administration of cisapride to rats on gestational day (GD) 13 caused digital reductions (8/108 fetuses, 4/9 litters) at 75 mg/kg and high incidence of embryonic death (55-82%) at 100-200 mg/kg. Identical developmental toxic effects have been described after temporary interruption of oxygen supply, and after single dose administration of selective I(Kr)-blockers, on the same GD. The results support the idea that all potent I(Kr)-blocking agents have the potential to cause embryolethality and teratogenicity, and that the adverse effects are mediated via hypoxic episodes due to embryonic arrhythmia.
Sköld
Anna-Carin
AC
Division of Toxicology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. anna-carin.skold@astrazeneca.com
Danielsson
Christian
C
Linder
Bengt
B
Danielsson
Bengt R
BR
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000196:embryology; D001549:Benzamides / Q000008:administration & dosage / Q000633:toxicity; D020117:Cisapride / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D005260:Female; D005318:Fetal Heart / Q000187:drug effects* / Q000503:physiopathology; D005311:Fetal Hypoxia / Q000139:chemically induced / Q000503:physiopathology; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000633:toxicity*; D009025:Morpholines / Q000008:administration & dosage / Q000633:toxicity; D009924:Organ Culture Techniques; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; D026902:Potassium Channel Blockers; C062720:mosapride; D020117:Cisapride