Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1987 May;55(5):509–512. doi: 10.1038/bjc.1987.103

Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours.

G Milano, M C Etienne, M Frenay, R Khater, J L Formento, N Renee, J L Moll, M Francoual, M Berto, M Namer
PMCID: PMC2001713  PMID: 3606944

Abstract

Recent biochemical and pharmacological findings concerning tamoxifen (TMX) have proven that both the unchanged drug and the main metabolites, N-desmethyltamoxifen (NDT) and 4-hydroxytamoxifen (4OHT) are biologically active. An HPLC method based on on-line post-column UV irradiation with fluorescence detection is described. Optimized conditions allowed complete and rapid separation of TMX 4OHT, NDT and two other recently reported metabolites, Y and Z. This method was applied to plasma and cytosol drug and metabolite analyses. In plasma, from the moment of initial drug administration until the steady state (after 1 month or more of continuous oral TMX treatment), the values of NDT to TMX ratios were completely reversed: 22 to 215 in mean %, P less than 0.01. The presence of metabolites Y and Z is significant. 4OHT, hardly detectable at the first dose, was measured at the steady state with high interpatient variability. It is hypothesized that metabolite evolution with time may be due to auto-induction of drug metabolism. In cytosols, which were all obtained during continuous TMX treatment, the ratios between TMX and metabolites were comparable to those observed in plasma, but with greater interpatient variability. Metabolite Y was not detectable in cytosols. This variability was not linked to the levels of cytosolic oestradiol receptors before initiation of treatment.

Full text

PDF
509

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adam H. K., Patterson J. S., Kemp J. V. Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers. Cancer Treat Rep. 1980 Jun-Jul;64(6-7):761–764. [PubMed] [Google Scholar]
  2. Briand P., Lykkesfeldt A. E. Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to growth at low serum concentration. Cancer Res. 1984 Mar;44(3):1114–1119. [PubMed] [Google Scholar]
  3. Camaggi C. M., Strocchi E., Canova N., Pannuti F. High-performance liquid chromatographic analysis of tamoxifen and major metabolites in human plasma. J Chromatogr. 1983 Jul 8;275(2):436–442. doi: 10.1016/s0378-4347(00)84393-5. [DOI] [PubMed] [Google Scholar]
  4. Daniel C. P., Gaskell S. J., Nicholson R. I. The measurement of tamoxifen and metabolites in the rat and relationship to the response of DMBA-induced mammary tumours. Eur J Cancer Clin Oncol. 1984 Jan;20(1):137–143. doi: 10.1016/0277-5379(84)90045-2. [DOI] [PubMed] [Google Scholar]
  5. Daniel P., Gaskell S. J., Bishop H., Campbell C., Nicholson R. I. Determination of tamoxifen and biologically active metabolites in human breast tumours and plasma. Eur J Cancer Clin Oncol. 1981 Nov;17(11):1183–1189. [PubMed] [Google Scholar]
  6. 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):765–773. [PubMed] [Google Scholar]
  7. Fabian C., Tilzer L., Sternson L. Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: correlation with blood levels in patients with metastatic breast cancer. Biopharm Drug Dispos. 1981 Oct-Dec;2(4):381–390. doi: 10.1002/bdd.2510020407. [DOI] [PubMed] [Google Scholar]
  8. Fernö M., Borg A. Antiestrogen binding sites in human breast cancer biopsies. Measurement ligand-specificity and affinity, and correlation to estrogen and progesterone receptors. Anticancer Res. 1985 May-Jun;5(3):307–312. [PubMed] [Google Scholar]
  9. Furr B. J., Jordan V. C. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther. 1984;25(2):127–205. doi: 10.1016/0163-7258(84)90043-3. [DOI] [PubMed] [Google Scholar]
  10. Golander Y., Sternson L. A. Paired-ion chromatographic analysis of tamoxifen and two major metabolites in plasma. J Chromatogr. 1980 Jan 11;181(1):41–49. doi: 10.1016/s0378-4347(00)81267-0. [DOI] [PubMed] [Google Scholar]
  11. Kemp J. V., Adam H. K., Wakeling A. E., Slater R. Identification and biological activity of tamoxifen metabolites in human serum. Biochem Pharmacol. 1983 Jul 1;32(13):2045–2052. doi: 10.1016/0006-2952(83)90425-2. [DOI] [PubMed] [Google Scholar]
  12. Milano G., Moll J. L., Formento J. L., Francoual M., Krebs B. P., Namer M., Boublil J. L., Lalanne C. M. Simultaneous micro measurement of steroid receptors in breast cancer. Br J Cancer. 1983 Oct;48(4):579–584. doi: 10.1038/bjc.1983.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Miller M. A., Lippman M. E., Katzenellenbogen B. S. Antiestrogen binding in antiestrogen growth-resistant estrogen-responsive clonal variants of MCF-7 human breast cancer cells. Cancer Res. 1984 Nov;44(11):5038–5045. [PubMed] [Google Scholar]
  14. Raam S., D'Agincourt P. G., Jordan V. C. A comparative study of electrophoretic mobilities of [3H]-estradiol and monohydroxytamoxifen binding components in the cytosols of human breast carcinomas and sera of healthy adult females. Eur J Cancer Clin Oncol. 1983 Oct;19(10):1457–1465. doi: 10.1016/0277-5379(93)90016-x. [DOI] [PubMed] [Google Scholar]
  15. Reddel R. R., Murphy L. C., Hall R. E., Sutherland R. L. Differential sensitivity of human breast cancer cell lines to the growth-inhibitory effects of tamoxifen. Cancer Res. 1985 Apr;45(4):1525–1531. [PubMed] [Google Scholar]
  16. Reddel R. R., Murphy L. C., Sutherland R. L. Effects of biologically active metabolites of tamoxifen on the proliferation kinetics of MCF-7 human breast cancer cells in vitro. Cancer Res. 1983 Oct;43(10):4618–4624. [PubMed] [Google Scholar]
  17. Reddel R. R., Sutherland R. L. Tamoxifen stimulation of human breast cancer cell proliferation in vitro: a possible model for tamoxifen tumour flare. Eur J Cancer Clin Oncol. 1984 Nov;20(11):1419–1424. doi: 10.1016/0277-5379(84)90062-2. [DOI] [PubMed] [Google Scholar]
  18. Sudo K., Monsma F. J., Jr, Katzenellenbogen B. S. Antiestrogen-binding sites distinct from the estrogen receptor: subecellular localization, ligand specificity, and distribution in tissues of the rat. Endocrinology. 1983 Feb;112(2):425–434. doi: 10.1210/endo-112-2-425. [DOI] [PubMed] [Google Scholar]
  19. Sutherland R. L., Murphy L. C. The binding of tamoxifen to human mammary carcinoma cytosol. Eur J Cancer. 1980 Sep;16(9):1141–1148. doi: 10.1016/0014-2964(80)90172-3. [DOI] [PubMed] [Google Scholar]
  20. Tate A. C., Greene G. L., DeSombre E. R., Jensen E. V., Jordan V. C. Differences between estrogen- and antiestrogen-estrogen receptor complexes from human breast tumors identified with an antibody raised against the estrogen receptor. Cancer Res. 1984 Mar;44(3):1012–1018. [PubMed] [Google Scholar]
  21. Taylor C. M., Blanchard B., Zava D. T. Estrogen receptor-mediated and cytotoxic effects of the antiestrogens tamoxifen and 4-hydroxytamoxifen. Cancer Res. 1984 Apr;44(4):1409–1414. [PubMed] [Google Scholar]
  22. Wilkinson P., Ribeiro G., Adam H., Patterson J. Clinical pharmacology of tamoxifen and N-desmethyltamoxifen in patients with advanced breast cancer. Cancer Chemother Pharmacol. 1980;5(2):109–111. doi: 10.1007/BF00435413. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES