DEVELOPMENTAL TOXICITY OF THE HMG-COA REDUCTASE INHIBITOR, ATORVASTATIN, IN RATS AND RABBITS

The developmental toxicity of the 3-hydroxy-3-methylgIutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, was investigated in pre gnant rats and rabbits given daily oral doses during organogenesis. Ra ts received 0, 10, 100, or 300 mg/kg on days 6-15 of gestation, and ra bbits received 0, 10, 50, or 100 mg/kg on days 6-18 of gestation. Mate rnal and fetal parameters were evaluated on day 20 (rats) or 29 (rabbi ts) of gestation. live fetuses were examined for external, visceral, a nd skeletal malformations and variations. At 300 mg/kg in rats, 1 trea tment-related death occurred on day 12 of gestation, and maternal body weight gain and food consumption were decreased during treatment (43% and 23%, respectively). In addition, animal at 300 mg/kg had total li tter resorption. Increased postimplantation loss (not statistically si gnificant) and slightly decreased fetal body weight (statistically sig nificant only in males) were also observed at 300 mg/kg. There were no significant differences between treated and control groups in the inc idence of fetal malformations or variations. No maternal or developmen tal toxicity was observed in rats at 10 or 100 mg/kg. In rabbits, mark ed maternal toxicity (7 deaths, body weight loss during and after trea tment, and decreased food consumption) and abortion occurred at 100 mg /kg. At 50 mg/kg, maternal toxicity (2 deaths and 72% body weight gain suppression) and abortion also occurred. There were no treatment-rela ted effects on live litter size or sex ratio. At 50 and 100 mg/kg, non statistically significant increases in postimplantation loss and decre ases in gravid uterine weight were observed, and at 100 mg/kg, decreas es in fetal body weight were observed relative to controls. There were no treatment-related malformations orvariations in live fetuses of at orvastatin-treated rabbits. No maternal or developmental toxicity was observed in rabbits at 10 mg/kg. Thus, these studies demonstrate devel opmental toxicity at maternally toxic doses of atorvastatin in rats an d rabbits, but no evidence of teratogenicity. (C) 1994 Wiley-Liss, Inc .