HYPOCHOLESTEROLEMIC ACTIVITY OF RALOXIFENE (LY139481) - PHARMACOLOGICAL CHARACTERIZATION AS A SELECTIVE ESTROGEN-RECEPTOR MODULATOR

After once-daily oral dosing in ovariectomized rats, raloxifene (LY139 481) hydrochloride produced dose- and time-dependent reductions in ser um cholesterol and high-density lipoprotein-cholesterol. Paired-feedin g studies demonstrated that effects of raloxifene on serum lipids were not secondary to effects on food consumption. Maximal reductions in s erum cholesterol occurred within 4 days of raloxifene administration o r sooner, depending on the administered dose. The ED(50) for 50% reduc tion in serum cholesterol by raloxifene was 0.13 +/- 0.04 mg/kg/day (m ean +/- S.E.M., n = 17); maximal cholesterol reduction by raloxifene ( 68%) was significantly less than that produced by estrogen (17 alpha-e thinylestradiol; 89%) after 4 to 7 days of daily dosing. Dose-response curves for cholesterol lowering by raloxifene were generated in the p resence of varying doses of 17 alpha-ethinylestradiol; two-way analysi s of variance revealed significant interactions between estrogen and r aloxifene with respect to cholestrol lowering (P < .001). Furthermore, a high dose of raloxifene (10 mg/kg/day) prevented further reduction of serum cholesterol by estrogen (1-100 mu g/kg/day) beyond that produ ced by raloxifene alone. For a series of closely related structural an alogs of raloxifene, log(ED(50)) values for cholesterol lowering were highly correlated with log(relative binding affinity) for the estrogen receptor (r = 0.93; P < .0001). Thus, cholesterol lowering by raloxif ene in ovariectomized rats is mediated primarily via partial agonist e ffects at estrogen receptors. Taken together with previous observation s in uterine tissue of estrogen antagonism by raloxifene in the absenc e of significant agonism, the present findings support the classificat ion of raloxifene as a selective estrogen receptor modulator.