THE SELECTIVE ESTROGEN-RECEPTOR MODULATOR, RALOXIFENE - AN OVERVIEW OF NONCLINICAL PHARMACOLOGY AND REPRODUCTIVE AND DEVELOPMENTAL TESTING

Raloxifene is a nonsteroidal, selective estrogen receptor modulator be ing developed by Eli Lilly and Company as a therapeutic agent for post menopausal osteoporosis. In the ovariectomized (OVX) rat, raloxifene p revents the loss of bone at the distal metaphysis of the femur, proxim al tibia, and vertebrae; reduces cancellous bone resorption; and reduc es serum cholesterol, but does not cause any significant changes in st romal eosinophilia or uterine epithelium In estrogen-stimulated OVX ra ts, raloxifene prevents the morning lowering of serum luteinizing horm one Levels, produces a reduction in afternoon serum prolactin levels, antagonizes pituitary weight increase, and antagonizes stimulation of mammary gland development. Raloxifene also has been shown to exhibit a ntiestrogenic activity in several in vivo and in vitro mammary tumor m odels. Raloxifene treatment results in regression of endometriosis in both a surgically prepared, rat uterine explant model and in Rhesus ma caques diagnosed with spontaneous endometriosis before exposure. Also, uterine leiomyomas in estrogen-stimulated OVX guinea pigs regress aft er the onset of raloxifene treatment. Raloxifene antagonizes testoster one-induced increases in prostate weight of castrated rats, but does n ot bind to androgen receptors or affect prostatic 5-alpha-reductase or testicular steroid 17-alpha-hydroxglase activity. A series of preclin ical toxicology studies was designed to characterize reproductive and developmental outcomes following various schedules of raloxifene treat ment in rats or rabbits. Studies of female reproduction and developmen tal outcome were conducted primarily at pharmacologic doses (0.1, 1, o r 10 mg/kg/d); male reproductive studies used higher doses (10, 30, or 100 mg/kg/d). In this series of studies, male reproductive end points were not affected, whereas embryo implantation, fetal rabbit morpholo gy, and several aspects of offspring development were disrupted by the lowest dose of maternal raloxifene treatment, a profile consistent wi th estrogen antagonist activity. (C) 1998 Elsevier Science Inc.