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 ca use developmental toxicity in the pregnant rabbit. Sotalol is a beta -adren oceptor blocking drug which also has class III antiarrhythmic properties vi a Ikr channel blockade. Experiment 1: Nine pregnant New Zealand White rabbi ts were given doses of either 300, 225, or 150 mg/kg of sotalol during gest ational days, called Days, 13-16 which resulted in total litter loss. Exper iment 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. Then w as marked increased embryonic death of 55-90% (four does with total litter loss), decreased number of live foetuses per litter, and elevated mean foet al 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 rang ed from total litter loss to similar to 30% at 50 mg/kg. At 50 mg/kg, the m aternal C-max, AUC(1-24 hr), and t(1/2) were approximately 45 muM, 340 mu m olxhr/1, 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 antiarrhy thmics) in rodents. The observed developmental toxicity in the rabbit is mo st likely secondary to embryonic arrhythmia as has been shown in rodent stu dies. The results may indicate that Ikr blocking agents are developmental t oxicants across species including man.