EVALUATION OF THE MAJOR METABOLITES OF RALOXIFENE AS MODULATORS OF TISSUE SELECTIVITY

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator ( SERM) which blocks the effects of estrogen on some tissues, such as th e breast and uterus, while mimicking estrogen in other tissues, such a s bone. To study the origins of this unique pharmacology, we have prep ared the major metabolites of raloxifene as chemical probes for examin ing the estrogen receptor function in vitro and in vivo. In human brea st cancer cell (MCF-7) related assays, these glucuronide conjugates sh ow little affinity for the estrogen receptor and are more than two ord ers of magnitude less potent at inhibiting cell proliferation than ral oxifene. In non-traditional estrogen target tissue, such as bone, thes e metabolites are less effective than the parent at inhibiting cytokin e-stimulated bone resorbing activity in rat osteoclasts or producing t ransforming growth factor beta-3 (TGF-beta(3)). In animal models, tiss ue distribution studies with radiolabelled metabolite indicate that co nversion to raloxifene occurs readily in a variety of tissues includin g the liver, lung, spleen, kidney, bone and uterus. Differential conve rsion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology d oes not result from tissue-selective deconjugation of metabolite to pa rent. (C) 1997 Elsevier Science Ltd.