Skip to main content
SpringerLink
Log in

Alterations in the Metabolism of Oestrogens During Treatment with Aminoglutethimide in Breast Cancer Patients

Preliminary Findings

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

In this small study, the effect of aminoglutethimide on the disposition of oestrogens in women with advanced breast cancer was investigated using bolus injections of 4-[14C]-oestradiol and 6,7-[3H]-oestrone sulphate, alone or in combination.

No alterations in oestrogen disposition were seen after short term (6 hours) aminoglutethimide administration. During long term (3 weeks to 8 months) aminoglutethimide treatment mean 4-[14C]-oestradiol clearance was not changed. 14C-Oestrone sulphate AUC was reduced by 43% at a low dose of aminoglutethimide (125mg twice daily) and by 65% at a high dose (250mg 4 times daily) with hydrocortisone acetate 25mg twice daily. The oestrone sulphate terminal elimination rate constant (λz) was concurrently increased (mean of 46 and 79%, respectively, with the 2 dosage regimens).

A possible increase in oestrone sulphate clearance during long term treatment was tested for by injecting 6,7-[3H]-oestrone sulphate. These studies revealed a marked increase (mean 104%) in oestrone sulphate clearance in patients receiving the high dose aminoglutethimide schedule.

Following injection of 4-[14C]-oestradiol plus 6,7-[3H]-oestrone sulphate, the fraction of 4-[14C]-oestradiol metabolised to oestrone sulphate was found to be reduced in all patients (mean 13%). A mean increase of 80% in the urinary excretion of 14C-oestriol was observed after 4-[14C]-oestradiol administration.

Our results, although preliminary, suggest that aminoglutethimide is a potent inducer of aminoglutethimide metabolism, thereby producing a significant reduction in plasma bioavailability of oestrone sulphate. These effects may have a role in the action of aminoglutethimide, a finding which warrants further investigation.

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

Similar content being viewed by others

References

  • Aboul-Enein A, Mansour N, Ashmawy I, Gawish Y, Abboud A. The influence of oestrogen receptor status on the response of metastatic breast cancer to aminoglutethimide. Second International Congress on Hormones and Cancer, Monte Carlo, 1983

    Google Scholar 

  • Barone RM, Shamonki IM, Siiteri PK, Judd HL. Inhibition of peripheral aromatization of androstenedione to estrone in postmenopausal women with breast cancer using Δ1-testololactone. Journal of Clinical Endocrinology and Metabolism 49: 672–676, 1979

    Article  PubMed  CAS  Google Scholar 

  • Bolt HM. Metabolism of estrogens — natural and synthetic. Pharmacology and Therapeutics 4: 155–181, 1979

    Article  PubMed  CAS  Google Scholar 

  • Bolt HM, Kappus H, Bolt M. Effect of rifampicin treatment on the metabolism of oestradiol and 17α-ethinyl-oestradiol by human liver microsomes. European Journal of Clinical Pharmacology 8: 301–307, 1975

    Article  PubMed  CAS  Google Scholar 

  • Breuer H, Knuppen R. Enzymes of estrogen metabolism. In Clayton RB (Ed.) Methods in enzymology, Vol. 15, Steroids and terpenoids, Academic Press, New York, 1969

    Google Scholar 

  • Conney AH, Levin W, Jacobson M, Kuntzman R. Effects of drugs and environmental chemicals on steroid metabolism. Clinical Pharmacology and Therapeutics 14: 727–741, 1973

    PubMed  CAS  Google Scholar 

  • Fishman J, Hellman L, Zumoff B, Cassouto J. Pathway and stereochemistry of the formation of estriols in man. Biochemistry 5: 1789–1794, 1966

    Article  PubMed  CAS  Google Scholar 

  • Fishman J, Hellman L, Zumoff B, Gallagher TF. Effect of thyroid on hydroxylation of estrogens in man. Journal of Clinical Endocrinology 25: 365–368, 1965

    Article  CAS  Google Scholar 

  • Flood C, Hunter SA, Lloyd CA, Longcope C. The effects of posture on the metabolism of androstenedione and estrone in males. Journal of Clinical Endocrinology and Metabolism 36: 1180–1188, 1973

    Article  PubMed  CAS  Google Scholar 

  • Gurpide E. Metabolic influences on the action of estrogens: therapeutic implications. Pediatrics 62 (Suppl.): 1114–1120, 1978

    PubMed  CAS  Google Scholar 

  • Gurpide E, Mann J, Lieberman S. Analysis of open systems of multiple pools by administration of tracers at a constant rate or as a single dose as illustrated by problems involving steroid hormones. Journal of Clinical Endocrinology and Metabolism 23: 1156–1176, 1963

    Google Scholar 

  • Harris AL, Dowsett M, Jeffcoate JA, McKinna M, Morgan M, et al. Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer. Journal of Clinical Endocrinology and Metabolism 55: 718–722, 1982

    Article  PubMed  CAS  Google Scholar 

  • Hellman L, Fishman J, Zumoff B, Cassouto J, Gallagher TF. Studies on estradiol transformation in women with breast cancer. Journal of Clinical Endocrinology 27: 1087–1089, 1967

    Article  CAS  Google Scholar 

  • Hembree WC, Bardin CW, Lipsett MB. A study of estrogen metabolic clearance rates and transfer factors. Journal of Clinical Investigation 48: 1809–1819, 1969

    Article  PubMed  CAS  Google Scholar 

  • Horky K, Kuchel O, Starka L, Gregorova I. Effect of aminoglutethimide on extraglandular metabolism of exogenous testosterone. Metabolism 20: 331–336, 1971

    Article  PubMed  CAS  Google Scholar 

  • Judd HL, Barone RM, Laufer LR, Gambone JC, Monfort SL, et al. In vivo effects of Δ1-testololactone on peripheral aromatization. Cancer Research 42 (Suppl.): 3345s–3348s, 1982

    PubMed  CAS  Google Scholar 

  • Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis and Rheumatism 22: 1195–1198, 1979

    Article  PubMed  CAS  Google Scholar 

  • Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Increased 16α-hydroxylation of estradiol in systemic lupus erythematosus. Journal of Clinical Endocrinology and Metabolism 53: 174–178, 1981

    Article  PubMed  CAS  Google Scholar 

  • Lisboa BP, Diczfalusy E. Separation and characterisation of steroid oestrogens by means of thin-layer chromatography. Acta Endocrinologica 40: 60–81, 1962

    PubMed  CAS  Google Scholar 

  • Longcope C. The metabolism of estrone sulfate in normal males. Journal of Clinical Endocrinology 34: 113–122, 1972

    Article  CAS  Google Scholar 

  • Longcope C, Billiar RB, Takaoka Y, Reddy SP, Hess D, et al. Tissue metabolism of estrogens in the female rhesus monkey. Endocrinology 109: 392–396, 1981

    Article  PubMed  CAS  Google Scholar 

  • Longcope C, Layne DS, Tait JF. Metabolic clearance rates and interconversions of estrone and 17β-estradiol in normal males and females. Journal of Clinical Investigation 47: 93–106, 1968

    Article  PubMed  CAS  Google Scholar 

  • Longcope C, Williams KIH. The metabolism of estrogens in normal women after pulse injections of 3H-estradiol and 3H-estrone. Journal of Clinical Endocrinology and Metabolism 38: 602–607, 1974

    Article  PubMed  CAS  Google Scholar 

  • Lønning PE, Kvinnsland S, Bakke OM. Effect of aminoglutethimide on antipyrine, theophylline and digitoxin disposition in breast cancer. Clinical Pharmacology and Therapeutics 36: 796–802, 1984a

    Article  PubMed  Google Scholar 

  • Lønning PE, Kvinnsland S, Jahren G. Aminoglutethimide and warfarin: a new important drug interaction. Cancer Chemotherapy and Pharmacology 12: 10–12, 1984b

    Article  PubMed  Google Scholar 

  • Lønning PE, Schanche JS, Kvinnsland S, Ueland PM. Single-dose and steady-state kinetics of aminoglutethimide. Clinical Pharmacokinetics 10: 353–364, 1985

    Article  PubMed  Google Scholar 

  • Lønning PE, Ueland PM, Kvinnsland S. The influence of a graded schedule of aminoglutethimide on the disposition of the optical enanthiomers of warfarin in patients with breast cancer. Cancer Chemotherapy and Pharmacology 17: 177–181, 1986

    Article  PubMed  Google Scholar 

  • Lu AYH, Levin W, Ryan D, West SB, Thomas P, et al. Induction of different types of cytochrome p-450 in liver microsomes by drugs and carcinogens. In Richens & Woodford (Eds) Anticonvulsant drugs and enzyme induction, Elsevier, Amsterdam, 1976

    Google Scholar 

  • Murray FT, Santner S, Samojlik E, Santen R. Serum aminoglutethimide levels: studies of serum half-life, clearance, and patient compliance. Journal of Clinical Pharmacology 19: 704–711, 1979

    PubMed  CAS  Google Scholar 

  • Myking O, Digranes A. Conjugated and unconjugated plasma oestrogens in men with chronic alcoholism and in normal men. Journal of Steroid Biochemistry 20: 799–801, 1984

    Article  PubMed  CAS  Google Scholar 

  • Myking O, Thorsen T, Støa KF. Conjugated and unconjugated plasma estrogens — oestrone, oestradiol and oestriol — in normal human males. Journal of Steroid Biochemistry 13: 1215–1220, 1980

    Article  PubMed  CAS  Google Scholar 

  • Nakamura Y, Ueda S. Induction of testosterone 16β-hydroxylase in rat liver microsomes by phenobarbital pretreatment. Biochemical and Biophysical Research Communications 93: 1014–1019, 1980

    Article  PubMed  CAS  Google Scholar 

  • Notelovitz M, Tjapkes J, Ware M. Interaction between estrogen and dilantin in a menopausal woman. New England Journal of Medicine 304: 788, 1981

    Article  PubMed  CAS  Google Scholar 

  • Roberts RK, Grice J, Wood L, Petroff V, McGuffie C. Cimetidine impairs the elimination of theophylline and antipyrine. Gastroenterology 81: 19–21, 1981

    PubMed  CAS  Google Scholar 

  • Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications, Lea and Febiger, Philadelphia, 1980

    Google Scholar 

  • Ruder HJ, Loriaux L, Lipsett MB. Estrone sulfate: production rate and metabolism in man. Journal of Clinical Investigation 51: 1020–1033, 1972

    Article  PubMed  CAS  Google Scholar 

  • Samojlik E, Santen RJ, Worgul TJ. Plasma estrone sulfate assessment of reduced estrogen production during treatment of metastatic breast carcinoma. Steroids 39: 497–507, 1982

    Article  PubMed  CAS  Google Scholar 

  • Samojlik E, Veldhuis JD, Wells SA, Santen RJ. Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma. Journal of Clinical Investigation 65: 602–612, 1980

    Article  PubMed  CAS  Google Scholar 

  • Sandberg AA, Slaunwhite WR. Studies on phenolic steroids in human subjects. II. The metabolic fate and hepatobiliary-enteric circulation of 14C-estrone and 14C-estradiol in women. Journal of Clinical Investigation 36: 1266–1278, 1957

    Article  PubMed  CAS  Google Scholar 

  • Santen RJ. Suppression of estrogens with aminoglutethimide and hydrocortisone (medical adrenalectomy) as treatment of advanced breast carcinoma: a review. Breast Cancer Research and Treatment 1: 183–202, 1981

    Article  PubMed  CAS  Google Scholar 

  • Santen RJ, Lipton A, Kendall J. Successful medical adrenalectomy with aminoglutethimide: role of altered drug metabolism. Journal of the American Medical Association 230: 1661–1665, 1974

    Article  PubMed  CAS  Google Scholar 

  • Santen RJ, Samojlik E, Wells SA. Resistance of the ovary to blockade of aromatization with aminoglutethimide. Journal of Clinical Endocrinology and Metabolism 51: 473–477, 1980

    Article  PubMed  CAS  Google Scholar 

  • Santen RJ, Santner S, Davis B, Veldhuis J, Samojlik E, et al. Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. Journal of Clinical Endocrinology and Metabolism 47: 1257–1265, 1978

    Article  PubMed  CAS  Google Scholar 

  • Santen RJ, Wells SA, Cohn N, Demers LM, Misbin RI, et al. Compensatory increase in TSH secretion without effect on prolactin secretion in patients treated with aminoglutethimide. Journal of Clinical Endocrinology and Metabolism 45: 739–746, 1977a

    Article  PubMed  CAS  Google Scholar 

  • Santen RJ, Wells SA, Runic S, Gupta C, Kendall J, et al. Adrenal suppression with aminoglutethimide. I. Differential effects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hydrocortisone. Journal of Clinical Endocrinology and Metabolism 45: 469–479, 1977b

    Article  PubMed  CAS  Google Scholar 

  • Santner SJ, Feil PD, Santen RJ. In situ estrogen production via the estrone sulfatase pathway in breast tumours: relative importance versus the aromatase pathway. Journal of Clinical Endocrinology and Metabolism 59: 29–33, 1984

    Article  PubMed  CAS  Google Scholar 

  • Schanche JS, Lønning PE, Ueland PM, Kvinnsland S. Determination of aminoglutethimide and N-acetylaminoglutethimide in human plasma by reversed-phase liquid chromatography. Therapeutic Drug Monitoring 6: 221–226, 1984

    Article  PubMed  CAS  Google Scholar 

  • Shackleton CHL, Whitney JO. Use of Sep-pak cartridges for urinary steroid extraction: evaluation of the method for use prior to gas chromatographic analysis. Clinica Chimica Acta 107: 231–243, 1980

    Article  CAS  Google Scholar 

  • Starka L, Motlik K, Horky K. The effect of aminoglutethimide on the metabolism of testosterone in rat liver in vitro. Journal of Steroid Biochemistry 2: 157–160, 1971

    Article  CAS  Google Scholar 

  • Støa KF, Skulstad PA. Biliary and urinary metabolites of intravenously and intraduodenally administered 17β-oestradiol and oestriol. Steroids and Lipids Research 3: 299–314, 1972

    PubMed  Google Scholar 

  • Vermeulen A, Paridaens R, Heuson JC. Effects of aminoglutethimide on adrenal steroid secretion. Clinical Endocrinology 19: 673–682, 1983

    Article  PubMed  CAS  Google Scholar 

  • Volk H, Deupree RH, Goldenberg IS, Wilde RC, Carabasi RA, et al. A dose response evaluation of delta-1-testololactone in advanced breast cancer. Cancer 33: 9–13, 1974

    Article  PubMed  CAS  Google Scholar 

  • Wander HE, Blossey HC, Nagel GA. Aminoglutethimide in the treatment of premenopausal patients with metastatic breast cancer. European Journal of Cancer and Clinical Oncology 22: 1371–1374, 1986

    Article  CAS  Google Scholar 

  • Wenzel M, Stahl H-J. Verstaerkte Hydroxylierung von Østrogenen beim Menschen nach Arzneimittelgabe nachweis durch HTO-Analyse des Kørperwassers. Hoppe-Seyler’s Zeitschrift für Physiologische Chemie 351: 761–762, 1970

    PubMed  CAS  Google Scholar 

  • Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390, 1975

    PubMed  CAS  Google Scholar 

  • Zumoff B, Fishman J, Cassouto J, Gallagher TF, Hellman L. Influence of age and sex on normal estradiol metabolism. Journal of Clinical Endocrinology 28: 937–941, 1968

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Biochemical Endocrinology, Oncology and Clinical Pharmacology Unit, Department of Pharmacology, University of Bergen, Bergen, Norway

    P. E. Lønning, S. Kvinnsland, T. Thorsen & P. M. Ueland

Authors
  1. P. E. Lønning
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Kvinnsland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Thorsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. M. Ueland
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lønning, P.E., Kvinnsland, S., Thorsen, T. et al. Alterations in the Metabolism of Oestrogens During Treatment with Aminoglutethimide in Breast Cancer Patients. Clin-Pharmacokinet 13, 393–406 (1987). https://doi.org/10.2165/00003088-198713060-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-198713060-00004

Keywords

Search

Navigation