THE SELECTIVE ESTROGEN-RECEPTOR MODULATOR, RALOXIFENE - SEGMENT-II STUDIES IN RATS AND RABBITS

Raloxifene is a nonsteroidal, selective estrogen receptor modulator de veloped by Eli Lilly and Company primarily as a therapeutic agent for postmenopausal osteoporosis. Two Segment II studies were conducted tha t examined maternal reproductive parameters and fetal outcome followin g gestational exposure to raloxifene, Pregnant CD rats (25/group) and New Zealand white rabbits (20/group) were dosed once daily by oral gav age with 0, 0.1, 1, or 10 mg/kg on Gestation Days (GD) 6 through 17 an d 7 through 19, respectively. Maternal body weight and food consumptio n were monitored throughout pregnancy. Caesarean sections were perform ed on GD 20 and GD 28 for rats and rabbits, respectively, to evaluate fetal viability, weight, and morphology, In rats, maternal body weight , body weight gain, and food consumption were reduced in all raloxifen e treatment groups. Fetal viability was depressed in the 10-mg/kg grou p and was often associated with signs of hemorrhaging from the vagina. Fetal growth retardation was indicated in the 1- and/or 10-mg/kg grou ps by increased incidences of fetal runts and the developmental deviat ions, wavy ribs and kidney cavitation, There was no evidence of treatm ent-related malformations in rat fetuses. In rabbits, depressions in b ody weight gain and food consumption occurred in the 10-mg/kg group, a nd a single abortion occurred in the 1-mg/kg group, Fetal viability an d weights were not affected in any of the raloxifene treatment groups. The overall proportions of fetuses with malformations, deviations, or variations were not affected by treatment with raloxifene; however, o ne fetus each from the 0,1-, 1-, and 10-mg/kg groups had incomplete cl osure of the interventricular septum, Therefore, maternal and fetal no -effect levels were not obtained in this study of raloxifene, (C) 1998 Elsevier Science Inc.