title: Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity.
abstract: Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology does not result from tissue-selective deconjugation of metabolite to parent.
authors.affiliation: Endocrine Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, U.S.A.
authors.forename: J A
authors.initials: JA
authors.lastname: Dodge
authors.forename: C W
authors.initials: CW
authors.lastname: Lugar
authors.forename: S
authors.initials: S
authors.lastname: Cho
authors.forename: L L
authors.initials: LL
authors.lastname: Short
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: N N
authors.initials: NN
authors.lastname: Yang
authors.forename: L A
authors.initials: LA
authors.lastname: Spangle
authors.forename: M J
authors.initials: MJ
authors.lastname: Martin
authors.forename: D L
authors.initials: DL
authors.lastname: Phillips
authors.forename: A L
authors.initials: AL
authors.lastname: Glasebrook
authors.forename: J J
authors.initials: JJ
authors.lastname: Osborne
authors.forename: C A
authors.initials: CA
authors.lastname: Frolik
authors.forename: H U
authors.initials: HU
authors.lastname: Bryant
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001862:Bone Resorption; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D005965:Glucuronates / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009928:Organ Specificity; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D020849:Raloxifene Hydrochloride; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D004965:Estrogen Antagonists; D005965:Glucuronates; D015850:Interleukin-6; D010880:Piperidines; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; C108481:raloxifene-4'-beta-glucuronide; C108482:raloxifene-6-beta-glucuronide; D020849:Raloxifene Hydrochloride; D004958:Estradiol