Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity

https://doi.org/10.1016/S0960-0760(97)00008-3Get rights and content

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-β3). 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.

References (30)

  • G.A. Colditz et al.

    The use of estrogens and progestins and the risk of breast cancer in postmenopausal women

    N. Engl. J. Med.

    (1995)
  • C.D. Jones et al.

    Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thlophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thienyl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity

    J. Med. Chem.

    (1984)
  • M.W. Draper et al.

    A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women

    J. Bone Min. Res.

    (1996)
  • M. Sato et al.

    Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats

    J. Pharmacol. Exp. Ther.

    (1996)
  • L.J. Black et al.

    Raloxfene (LY139478 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats

    J. Clin. Invest.

    (1994)
  • Cited by (56)

    • Sulfonation of raloxifene in HEK293 cells overexpressing SULT1A3: Involvement of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in excretion of sulfate metabolites

      2015, Drug Metabolism and Pharmacokinetics
      Citation Excerpt :

      Since raloxifene glucuronides are found in blood in an old report, previous metabolism studies have mainly focused on glucuronidation, giving less attention to other metabolic pathways such as sulfonation [21]. However, there is accumulating evidence that sulfonation plays an important role in disposition of raloxifene in human tissues [20,22,23]. Analysis of sulfonation pathway will help to understand the mechanisms of raloxifene [20].

    • Effect of UDP-glucuronosyltransferase 1A8 polymorphism on raloxifene glucuronidation

      2013, European Journal of Pharmaceutical Sciences
      Citation Excerpt :

      In addition, these clinical studies have reported that the products of in vivo metabolism are glucuronides at 6- and/or 4′-positions of raloxifene, and that the plasma concentration of 4′-glucuronide is about 8-fold higher than that of 6-glucuronide. The glucuronides exhibit minimal binding to estrogen receptor but they should not be overlooked as they can be readily reconverted to active raloxifene in various organs (Dodge et al., 1997). Raloxifene glucuronidation has been identified to be catalyzed by UGT1A1, UGT1A8, UGT1A9 and UGT1A10 in humans (Fig. 1) (Kemp et al., 2002).

    View all citing articles on Scopus
    View full text