Pre- and postnatal toxicity of the HMG-CoA reductase inhibitor atorvastatin in rats.
Atorvastatin is a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of 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 important contributions to the maternal animal during pregnancy and lactation, as well as to the growth and development of the offspring; these contributions may potentially be influenced by inhibition of HMG-CoA reductase. 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 lactation day 20. Maternal toxicity, characterized by morbidity/mortality (13%), reduced body weight gain and food consumption, and pathologic lesions in the nonglandular mucosa of the stomach, occurred at 225 mg/kg. Offspring survival at birth and during the neonatal period at 225 mg/kg was reduced relative to control by up to 45%, and 28% of litters had no viable offspring by 10 days postpartum. Additional effects on offspring included reduced body weight during the neonatal and maturation periods (100, 225 mg/kg), delayed appearance of pinnae detachment and incisor eruption (225 mg/kg), impaired rotorod performance (females only; 100, 225 mg/kg), reduced acoustic startle responding (males only; 20, 100, 225 mg/kg), and transient effects on shuttle avoidance (females only; 225 mg/kg). No treatment-related effects were observed on offspring reproduction. In a separate experiment, a single dose of 10 mg/kg atorvastatin administered to female Wistar rats on gestation day 19 or lactation day 13 provided evidence of placental transfer and excretion into the milk. Results of this study indicate that pre- and postnatal administration of atorvastatin to female rats produces developmental toxicity in their offspring via in utero and/or lactational exposure, and in the presence or absence of maternal toxicity.
Henck
J W
JW
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Craft
W R
WR
Black
A
A
Colgin
J
J
Anderson
J A
JA
D000818:Animals; D019540:Area Under Curve; D000069059:Atorvastatin; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006538:Heptanoic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D007774:Lactation / Q000187:drug effects*; D008297:Male; D004856:Postural Balance / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011297:Prenatal Exposure Delayed Effects; D011758:Pyrroles / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D015996:Survival Rate; D014018:Tissue Distribution
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin