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Vol. 280, Issue 1, 146-153, 1997

Hypocholesterolemic Activity of Raloxifene (LY139481): Pharmacological Characterization as a Selective Estrogen Receptor Modulator

Raymond F. Kauffman, William R. Bensch, Roger E. Roudebush, Harlan W. Cole, James S. Bean, D. Lynn Phillips, Amy Monroe, George J. Cullinan, Andrew L. Glasebrook and Henry U. Bryant

Divisions of Cardiovascular Research (R.F.K., W.R.B., J.S.B.) and Endocrine Research (R.E.R., H.W.C., D.L.P., A.M., G.J.C., A.L.G., H.U.B.), Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana

After once-daily oral dosing in ovariectomized rats, raloxifene (LY139481) hydrochloride produced dose- and time-dependent reductions in serum cholesterol and high-density lipoprotein-cholesterol. Paired-feeding studies demonstrated that effects of raloxifene on serum lipids were not secondary to effects on food consumption. Maximal reductions in serum cholesterol occurred within 4 days of raloxifene administration or sooner, depending on the administered dose. The ED50 for 50% reduction in serum cholesterol by raloxifene was 0.13 ± 0.04 mg/kg/day (mean ± S.E.M., n = 17); maximal cholesterol reduction by raloxifene (68%) was significantly less than that produced by estrogen (17alpha -ethinylestradiol; 89%) after 4 to 7 days of daily dosing. Dose-response curves for cholesterol lowering by raloxifene were generated in the presence of varying doses of 17alpha -ethinylestradiol; two-way analysis of variance revealed significant interactions between estrogen and raloxifene 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 µg/kg/day) beyond that produced by raloxifene alone. For a series of closely related structural analogs of raloxifene, log(ED50) 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 raloxifene in ovariectomized rats is mediated primarily via partial agonist effects at estrogen receptors. Taken together with previous observations in uterine tissue of estrogen antagonism by raloxifene in the absence of significant agonism, the present findings support the classification of raloxifene as a selective estrogen receptor modulator.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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