Embryotoxic effects of L-691,121, a class III antiarrhythmic agent, in rats.
L-691,121 is a class III antiarrhythmic agent which blocks potassium currents, leading to prolongation of cardiac potential and prevention of cardiac arrhythmia. In a developmental toxicity study in rats, there was a dose-dependent decrease in embryonic/fetal survival, and death of the entire litter was seen at an oral dose of 0.8 mg/kg per day. The critical period for embryolethality was determined as gestational days (GD) 10-13. In a study where females received 1 mg/kg on a critical day (GD 10 or 12) and were killed at 24-h intervals, a high embryonic mortality was seen at 72 h (GD 10 treatment) or 48 h (GD 12 treatment) after dosing. The surviving embryos had morphological abnormalities such as enlarged cardiac tube and pericardium, generalized edema, and hematoma. In order to investigate a possible mechanism for the embryolethality, GD 11 embryos were dissected from females at 4 h after dosing of 1 mg/kg and incubated for 5 h in vitro. The embryonic heart rates were decreased for the first 2 h after incubation but tended to recover to control levels thereafter. When GD 11 embryos were incubated for 4 h with the drug, there were decreases in the heart rates during the entire observation period. In a washout study where the embryos were transferred to drug-free medium after 1-h exposure, decreased heart rates recovered to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Ban
Y
Y
Development Research Laboratories, Banyu Pharmaceutical Co., Ltd. Saitama, Japan.
Konishi
R
R
Kawana
K
K
Nakatsuka
T
T
Fujii
T
T
Manson
J M
JM
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D006332:Cardiomegaly / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects* / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced / Q000401:mortality; D005865:Gestational Age; D006340:Heart Rate, Fetal / Q000187:drug effects; D006406:Hematoma / Q000139:chemically induced; D008297:Male; D010496:Pericardium / Q000187:drug effects / Q000473:pathology; D010881:Piperidones / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000008:administration & dosage / Q000633:toxicity*
D000889:Anti-Arrhythmia Agents; D010881:Piperidones; D013141:Spiro Compounds; C077569:L 691121