Skip to main content
SpringerLink
Log in

Pharmacokinetics of Selective Estrogen Receptor Modulators

  • Review Article
  • Drug Disposition
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Selective estrogen receptor modulators (SERMs) are a class of compounds used to treat and prevent breast cancer and osteoporosis. SERMs currently approved for use in patients include tamoxifen, toremifene and raloxifene. These compounds are well tolerated in patients, and the most common adverse effects experienced in patients undergoing SERM therapy include vasomotor symptoms such as hot flashes and vaginal discharge. New SERMs currently under development for use in the treatment and prevention of osteoporosis and breast cancer include ospemifene, a derivative of toremifene, and arzoxifene, a compound very similar in structure to raloxifene.

SERMs are administered orally at doses ranging from 20 to 60 mg/day. Tamoxifen and toremifene have a bioavailability of approximately 100%, whereas that of raloxifene is only 2%. SERMs are very highly bound to plasma proteins (>95%). Tamoxifen and toremifene are metabolised by the cytochrome P450 enzyme system, and raloxifene is metabolised by glucuronide conjugation. The terminal elimination half-lives of these drugs range from 27.7 hours to 7 days. The pharmacokinetics of these compounds are affected in hepatically impaired patients, but not in renally impaired patients. SERMs have several potential drug interactions with other agents, such as warfarin, rifampicin (rifampin), cholestyramine and aromatase inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II

Similar content being viewed by others

References

  1. Snyder KR, Sparano N, Malinowski JM. Raloxifene hydrochloride. Am J Health Syst Pharm 2000 Sep; 57(18): 1669–78

    PubMed  CAS  Google Scholar 

  2. Taras TL, Wurz GT, DeGregorio MW. In vitro and in vivo biologic effects of ospemifene (FC-1270a) in breast cancer. J Steroid Biochem Mol Biol 2001 Jun; 77(4–5): 271–9

    Article  PubMed  CAS  Google Scholar 

  3. Wenger NK, Grady D. Postmenopausal hormone therapy, SERMs, and coronary heart disease in women. J Endocrinol Invest 1999 Sep; 22(8): 616–24

    PubMed  CAS  Google Scholar 

  4. Taras TL, Wurz GT, Linares GR, et al. Clinical pharmacokinetics of toremifene. Clin Pharmacokinet 2000 Nov; 39(5): 327–34

    Article  PubMed  CAS  Google Scholar 

  5. Marttunen MB, Hietanen P, Tiitinen A, et al. Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 1998 Apr; 83(4): 1158–62

    Article  PubMed  CAS  Google Scholar 

  6. Qu Q, Zheng H, Dahllund J, et al. Selective estrogenic effects of a novel triphenylethylene compound, PC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology 2000 Feb; 141(2): 809–20

    Article  PubMed  CAS  Google Scholar 

  7. Sato M, Turner CH, Wang T, et al. LY353381.HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. J Pharmacol Exp Ther 1998 Oct; 287(1): 1–7

    PubMed  CAS  Google Scholar 

  8. Fuchs WS, Leary WP, van der Meer MJ, et al. Pharmacokinetics and bioavailability of tamoxifen in postmenopausal healthy women. Arzneimittel Forschung 1996 Apr; 46(4): 418–22

    PubMed  CAS  Google Scholar 

  9. Buzdar AU, Hortobagyi GN. Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy. J Clin Oncol 1998 Jan; 16(1): 348–53

    PubMed  CAS  Google Scholar 

  10. Fisher B, Costantino JP, Lawrence D, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998 Sep; 90(18): 1371–88

    Article  PubMed  CAS  Google Scholar 

  11. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med 1988 Aug; 109(3): 219–28

    PubMed  CAS  Google Scholar 

  12. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992 Mar; 326(13): 852–6

    Article  PubMed  CAS  Google Scholar 

  13. Saarto T, Blomqvist C, Ehnholm C, et al. Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer. J Clin Oncol 1996 Feb; 14(2): 429–33

    PubMed  CAS  Google Scholar 

  14. Gershanovich M, Garin A, Baltina D, et al. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat 1997 Sep; 45(3): 251–62

    Article  PubMed  CAS  Google Scholar 

  15. Holli K. Adjuvant trials of toremifene vs tamoxifen: the European experience. Oncology 1998 Mar; 12 (3 Suppl. 5): 23–7

    PubMed  CAS  Google Scholar 

  16. Gams R. Phase III trials of toremifene vs tamoxifen. Oncology 1997 May; 11 (5 Suppl. 4): 23–8

    PubMed  CAS  Google Scholar 

  17. Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen treated breast cancer patients: findings from the National Adjuvant Breast and Bowel Project (NSAPB-14). J Natl Cancer Inst 1994 Apr; 86(7): 527–37

    Article  PubMed  CAS  Google Scholar 

  18. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997 Dec; 337(23): 1641–7

    Article  PubMed  CAS  Google Scholar 

  19. Muchmore DB. Raloxifene: a selective estrogen receptor modulator (SERM) with multiple target system effects. Oncologist 2000; 5(5): 388–92

    Article  PubMed  CAS  Google Scholar 

  20. Meunier PJ, Vignot E, Garnero P, et al. Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Osteoporos Int 1999; 10(4): 330–6

    Article  PubMed  CAS  Google Scholar 

  21. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999 Aug; 282(7): 637–45

    Article  PubMed  CAS  Google Scholar 

  22. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998 May; 279(18): 1445–51

    Article  PubMed  CAS  Google Scholar 

  23. Scott JA, Camara CC, Early JE. Raloxifene: a selective estrogen receptor modulator. Am Fam Physician 1999 Sep; 60(4): 1131–9

    PubMed  CAS  Google Scholar 

  24. DeGregorio MW, Wurz GT, Taras TL, et al. Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator. Eur J Clin Pharmacol 2000 Sep; 56(6–7): 469–75

    Article  PubMed  CAS  Google Scholar 

  25. Viopio SK, Komi J, Kangas L, et al. Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. Maturitas 2002; 43: 207–14

    Article  Google Scholar 

  26. Münster PN, Buzdar A, Dhingra K, et al. Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer. J Clin Oncol 2001 Apr; 19(7): 2002–9

    PubMed  Google Scholar 

  27. Schafer JM, Lee ES, Dardes RC, et al. Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts. Clin Cancer Res 2001 Aug; 7(8): 2505–12

    PubMed  CAS  Google Scholar 

  28. Guelen PJM, Stevenson D, Briggs RJ, et al. The bioavailability of Tamoplex (tamoxifen): Part 2. a single dose cross-over study in healthy male volunteers. Methods Find Exp Clin Pharmacol 1987 Oct; 9(10): 685–90

    PubMed  CAS  Google Scholar 

  29. Buckley MMT, Goa KL. Tamoxifen: a reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use. Drugs 1989 Apr; 37(4): 451–90

    Article  PubMed  CAS  Google Scholar 

  30. Kemp JV, Adam HK, Wakeling AE, et al. Identification and biological activity of tamoxifen metabolites in human serum. Biochem Pharmacol 1983 Jul; 32(13): 2045–52

    Article  PubMed  CAS  Google Scholar 

  31. Wilkinson P, Ribeiro G, Adam H, et al. Clinical pharmacology of tamoxifen and N-desmethyltamoxifen in patients with advanced breast cancer. Cancer Chemother Pharmacol 1980; 5(2): 109–11

    Article  PubMed  CAS  Google Scholar 

  32. Anttila M, Laakso S, Nyländen P, et al. Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function. Clin Pharmacol Ther 1995 Jun; 57(6): 628–35

    Article  PubMed  CAS  Google Scholar 

  33. Wiebe VJ, Benz CC, Shemano I, et al. Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer. Cancer Chemother Pharmacol 1990; 25(4): 247–51

    Article  PubMed  CAS  Google Scholar 

  34. Kohler P, Hamm JT, Wiebe VJ, et al. Phase I study of the tolerance and pharmacokinetics of toremifene in patients with cancer. Breast Cancer Res Treat 1990 Aug; 16 Suppl. 1: S19–26

    Article  PubMed  Google Scholar 

  35. Evista® (raloxifene hydrochloride): package insert. Indianapolis (IN): Lilly, 1998

  36. Wiebe VJ, Benz CC, DeGregorio MW. Clinical pharmacokinetics of drugs used in the treatment of breast cancer. Clin Pharmacokinet 1988 Sep; 15(3): 180–93

    Article  PubMed  CAS  Google Scholar 

  37. Bonanni B, Harriet J, Gandini S, et al. Effect of low dose tamoxifen on the insulin-like growth factor system in healthy women. Breast Cancer Res Treat 2001 Sep; 69(1): 21–7

    Article  PubMed  CAS  Google Scholar 

  38. Tukker JJ, Blankenstein MA, Nortier JWR. Comparison of bioavailability in man of tamoxifen after oral and rectal administration. J Pharm Pharmacol 1986 Dec; 38(12): 888–92

    Article  PubMed  CAS  Google Scholar 

  39. Anttila M, Valavaara R, Kivinen S, et al. Pharmacokinetics of toremifene. J Steroid Biochem 1990 Jun; 36(3): 249–52

    Article  PubMed  CAS  Google Scholar 

  40. Herrlinger C, Braunfels M, Fink E, et al. Pharmacokinetics and bioavailability of tamoxifen in healthy volunteers. Int J Clin Phamacol Ther Toxicol 1992 Nov; 30(11): 487–9

    CAS  Google Scholar 

  41. Lien EA, Solheim E, Lea OA, et al. Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 1989 Apr; 49(8): 2175–83

    PubMed  CAS  Google Scholar 

  42. Wiseman LR, Goa KL. Toremifene: a review of its pharmacological properties and clinical efficacy in the management of advanced breast cancer. Drugs 1997 Jul; 54(1): 141–60

    Article  PubMed  CAS  Google Scholar 

  43. Fabian C, Sternson L, Barnett M. Clinical pharmacology of tamoxifen in patients with breast cancer: comparison of traditional and loading dose schedules. Cancer Treat Rep 1980 Jun-Jul; 64(6–7): 765–73

    PubMed  CAS  Google Scholar 

  44. Sipilä H, Näntö V, Kangas L, et al. Binding of toremifene to human serum proteins. Pharmacol Toxicol 1988 Jul; 63(1): 62–4

    Article  PubMed  Google Scholar 

  45. Wilking N, Appelgren LE, Carlstrom K, et al. The distribution and metabolism of 14C-labelled tamoxifen in spayed female mice. Acta Pharmacol Toxicol 1982; 50(3): 161–8

    Article  CAS  Google Scholar 

  46. Lien EA, Solheim E, Ueland PM. Distribution of tamoxifen and its metabolites in rat and human tissue during steady-state treatment. Cancer Res 1991 Sep; 51(18): 4837–44

    PubMed  CAS  Google Scholar 

  47. Fromson JM, Sharp DS. The selective uptake of tamoxifen by human uterine tissue. J Obstet Gynaecol 1974 Apr; 81(4): 321–3

    CAS  Google Scholar 

  48. Fromson JM, Pearson S, Bramah S. The metabolism of tamoxifen (I.C.I. 46,474): II. in female patients. Xenobiotica 1973 Nov; 3(11): 711–4

    Article  PubMed  CAS  Google Scholar 

  49. Lønning PE, Lien EA, Lundgren S, et al. Clinical pharmacokinetics of endocrine agents used in advanced breast cancer. Clin Pharmacokinet 1992 May; 22(5): 327–58

    Article  PubMed  Google Scholar 

  50. Kangas L, Haaparanta M, Paul R, et al. Biodistribution and scintigraphy of 11C-toremifene in rats bearing DMBA-in-duced mammary carcinoma. Pharmacol Toxicol 1989 Apr; 64(4): 373–7

    Article  PubMed  CAS  Google Scholar 

  51. Sotaniemi EA, Anttila MI. Influence of age on toremifene pharmacokinetics. Cancer Chemother Pharmacol 1997; 40(2): 185–8

    Article  PubMed  CAS  Google Scholar 

  52. Wiseman H, Lewis DFV. The metabolism of tamoxifen by human cytochromes P450 is rationalized by molecular modeling of the enzyme-substrate interactions: potential importance to its proposed anti-carcinogenic/carcinogenic actions. Carcinogenesis 1996 Jun; 17(6): 1357–60

    Article  PubMed  CAS  Google Scholar 

  53. Berthou F, Dreano Y, Belloc C, et al. Involvement of cytochrome P450 3A enzyme family in the major metabolic pathways of toremifene in human liver microsomes. Biochem Pharmacol 1994 May; 47(10): 1883–95

    Article  PubMed  CAS  Google Scholar 

  54. Meltzer NM, Stang P, Sternson LA. Influence of tamoxifen and its N-desmethyl and 4-hydroxy metabolites on rat liver microsomal enzymes. Biochem Pharmacol 1984 Jan; 33(1): 115–23

    Article  PubMed  CAS  Google Scholar 

  55. Adam HK, Patterson JS, Kemp JV. Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers. Cancer Treat Rep 1980 Jun–Jul; 64(6–7): 761–4

    PubMed  CAS  Google Scholar 

  56. Dehal SS, Kupfer D. Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metab Dispos 1999 Jun; 27(6): 681–8

    PubMed  CAS  Google Scholar 

  57. Coezy E, Borgna JL, Rochefort H. Tamoxifen and metabolites in MCF7 cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res 1982 Jan; 42(1): 317–23

    PubMed  CAS  Google Scholar 

  58. Kangas L. Biochemical and pharmacological effects of toremifene metabolites. Cancer Chemother Pharmacol 1990; 27(1): 8–12

    Article  PubMed  CAS  Google Scholar 

  59. Bishop J, Murray R, Webster L, et al. Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer. Cancer Chemother Pharmacol 1992; 30(3): 174–8

    Article  PubMed  CAS  Google Scholar 

  60. Ducharme J, Fried K, Shenouda G, et al. Tamoxifen metabolic patterns within a glioma patient population treated with highdose tamoxifen. Br J Clin Pharmacol 1997 Feb; 43(2): 189–93

    Article  PubMed  CAS  Google Scholar 

  61. Furr BJA, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25(2): 127–205

    Article  PubMed  CAS  Google Scholar 

  62. McVie JG, Simonetti GP, Stevenson D, et al. The bioavailability of Tamoplex (tamoxifen): Part 1. a pilot study. Methods Find Exp Clin Pharmacol 1986 Aug; 8(8): 505–12

    PubMed  CAS  Google Scholar 

  63. Knadler MP, Lantz RJ, Gillespie TA, et al. The disposition and metabolism of 14C-labeled raloxifene in humans [abstract]. Pharm Res 1995; 12 Suppl. 1: 372

    Google Scholar 

  64. Hochner-Celnikier D. Pharmacokinetics of raloxifene and its clinical application. Eur J Cancer 1999 Jul; 85(1): 23–9

    CAS  Google Scholar 

  65. Sutherland CM, Sternson LA, Muchmore JH, et al. Effect of impaired renal function on tamoxifen. J Surg Oncol 1984 Dec; 27(4): 222–3

    Article  PubMed  CAS  Google Scholar 

  66. DeGregorio MW, Wiebe VJ, Venook AP, et al. Elevated plasma tamoxifen levels in a patient with liver obstruction. Cancer Chemother Pharmacol 1989; 23(3): 194–5

    Article  PubMed  CAS  Google Scholar 

  67. Peyrade F, Frenay M, Etienne MC, et al. Age related difference in tamoxifen disposition. Clin Pharmacol Ther 1996 Apr; 59(4): 401–10

    Article  PubMed  CAS  Google Scholar 

  68. Tenni P, Lalich DL, Byrne MJ. Life threatening interaction between tamoxifen and warfarin [letter]. BMJ 1989 Jan; 298(6666): 93

    Article  PubMed  CAS  Google Scholar 

  69. Kivistö KT, Villikka K, Nyman L, et al. Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther 1998 Dec; 64(6): 648–54

    Article  PubMed  Google Scholar 

  70. Lien EA, Lønning PE, Solheim E, et al. Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res 1990 Sep; 50(18): 5851–7

    PubMed  CAS  Google Scholar 

  71. Dowsett M, Pfister C, Johnston SRD, et al. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 1999 Sep; 5(9): 2338–43

    PubMed  CAS  Google Scholar 

  72. Ingle JN, Suman VJ, Johnson PA, et al. Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. Clin Cancer Res 1999 Jul; 5(7): 1642–9

    PubMed  CAS  Google Scholar 

  73. Miller JW, Skerjanec A, Knadler MP, et al. Divergent effects of raloxifene HCl on the pharmacokinetics and pharmacodynamics of warfarin. Pharm Res 2001 Jul; 18(7): 1024–8

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Mrs Bell Keithly for contributing to the fluidity of the final manuscript. Dr DeGregorio has served as a consultant for pharmaceutical companies involved in the development of SERMs.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology/Oncology, University of California, Cancer Center, 4501 X Street Room 3016, Davis, Sacramento, California, 95817, USA

    Karla C. Morello, Gregory T. Wurz &  Michael W. DeGregorio

Authors
  1. Karla C. Morello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory T. Wurz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael W. DeGregorio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael W. DeGregorio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morello, K.C., Wurz, G.T. & DeGregorio, M.W. Pharmacokinetics of Selective Estrogen Receptor Modulators. Clin Pharmacokinet 42, 361–372 (2003). https://doi.org/10.2165/00003088-200342040-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200342040-00004

Keywords

Search

Navigation