Developmental toxicity in the pregnant rabbit by the class III antiarrhythmic drug sotalol.
The purpose of this study was to investigate the potential of sotalol to cause developmental toxicity in the pregnant rabbit. Sotalol is a beta-adrenoceptor blocking drug which also has class III antiarrhythmic properties via Ikr channel blockade. EXPERIMENT 1: Nine pregnant New Zealand White rabbits were given doses of either 300, 225, or 150 mg/kg of sotalol during gestational days, called Days, 13-16 which resulted in total litter loss. EXPERIMENT 2: A single dose of sotalol, 100 or 150 mg/kg was administered during Days 8-17 to 15 rabbits. Dosing on Day 8, 9, or 10 resulted in a slightly higher incidence of embryonic death compared to historical controls. There was marked increased embryonic death of 55-90% (four does with total litter loss), decreased number of live foetuses per litter, and elevated mean foetal weight after dosing during Days 12-16. EXPERIMENT 3: 16 pregnant rabbits were administered single doses of sotalol of either 100, 85, 75, 60 or 50 mg/kg on Day 14. The main finding was increased embryonic death, which ranged from total litter loss to approximately 30% at 50 mg/kg. At 50 mg/kg, the maternal Cmax, AUC(1-24 hr), and t1/2 were approximately 45 microM, 340 micromol x hr/l, and 6 hr, respectively. In conclusion, sotalol treatment resulted in embryonic death in the rabbit in early pregnancy in the same way as has been seen for other drugs with Ikr blocking properties (class III antiarrhythmics) in rodents. The observed developmental toxicity in the rabbit is most likely secondary to embryonic arrhythmia as has been shown in rodent studies. The results may indicate that Ikr blocking agents are developmental toxicants across species including man.
Sköld
A C
AC
Department of Pharmaceutical Biosciences Uppsala University, Sweden. anna-carin.skold@astrazeneca.com
Danielsson
B R
BR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D020964:Embryo Loss / Q000139:chemically induced; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D020567:Fetal Weight / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D011247:Pregnancy; D011817:Rabbits; D013015:Sotalol / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D018675:Toxicity Tests
D000889:Anti-Arrhythmia Agents; D013015:Sotalol