PRE-NATAL AND POSTNATAL TOXICITY OF THE HMG-COA REDUCTASE INHIBITOR ATORVASTATIN IN RATS

Atorvastatin is a potent inhibitor of the enzyme 3-hydroxy-3-methylglu taryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion o f HMG-CoA to mevalonate and constitutes the rate-limiting step in the biosynthesis of cholesterol. Steroid hormones derived from cholesterol , as well as mevalonate and its isoprenoid derivatives, provide import ant contributions to the maternal animal during pregnancy and lactatio n, as well as to the growth and development of the offspring; these co ntributions may potentially be influenced by inhibition of HMG-CoA red uctase. To investigate the effects of atorvastatin on various aspects of reproduction and development, female Sprague-Dawley rats received 0 , 20, 100, or 225 mg/kg daily by gavage from gestation day 7 through l actation day 20. Maternal toxicity, characterized by morbidity/mortali ty (13%), reduced body weight gain and food consumption, and pathologi c lesions in the nonglandular mucosa of the stomach, occurred at 225 m g/kg. Offspring survival at birth and during the neonatal period at 22 5 mg/kg was reduced relative to control by up to 45%, and 28% of litte rs had no viable offspring by 10 days postpartum Additional effects on offspring included reduced body weight during the neonatal and matura tion periods (100, 225 mg/kg), delayed appearance of pinnae detachment and incisor eruption (225 mg/kg), impaired rotorod performance (femal es only; 100, 225 mg/kg), reduced acoustic startle responding (males o nly; 20, 100, 225 mg/kg), and transient effects on shuttle avoidance ( females only; 225 mg/kg). No treatment-related effects were observed o n offspring reproduction. In a separate experiment, a single dose of 1 0 mg/kg atorvastatin administered to female Wistar rats on gestation d ay 19 or lactation day 13 provided evidence of placental transfer and excretion into the milk. Results of this study indicate that pre-and p ostnatal administration of atorvastatin to female rats produces develo pmental toxicity in their offspring via in utero and/or lactational ex posure, and in the presence or absence of maternal toxicity. (C) 1998 Society of Toxicology.