Effects of glucokinase activator, DS-7309, on embryo-fetal developmental toxicity in rats and rabbits

The toxicological effects of DS-7309, a glucokinase activator, on pregnancy and embryo-fetal development in rats and rabbits and maternal blood glucose levels were examined. DS-7309 was administered at 3, 10, or 100 mg/kg to rats from Days 7-17 of pregnancy or at 10, 30, or 100 mg/kg to rabbits from Days 6-18 of pregnancy. In rats, maternal hypoglycemia (approximately 50 mg/dL) was seen at 3 and 10 mg/kg, but it recovered 7 h after dosing, leading to no toxic changes. In contrast, continuous severe maternal hypoglycemia (approximately 40 mg/dL, >= 7 h), fetal eye anomalies, and decreased fetal body weight were noted at 100 mg/kg. In rabbits, no fetal anomalies were seen at 10 and 30 mg/kg where maternal blood glucose level dropped to approximately 60-90 mg/dL, but recovered by 7 h after dosing at the latest. In contrast, at 100 mg/kg, severe hypoglycemia (around 60 mg/dL) was maintained and did not recover until 24 h after dosing; it resulted in decreased fetal viability and increased fetal skeleton anomalies. These findings indicate that DS-7309 could lead to embryo-fetal toxicity in rats and rabbits, with such toxicity considered to be related to continuous severe maternal hypoglycemia.