Clinical Pharmacokinetics

, Volume 13, Issue 6, pp 393–406 | Cite as

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

Preliminary Findings
  • P. E. Lønning
  • S. Kvinnsland
  • T. Thorsen
  • P. M. Ueland
Original Research Article


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.


Advanced Breast Cancer Clinical Endocrinology Oestriol Santen Aminoglutethimide 
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  1. 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, 1983Google Scholar
  2. 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, 1979PubMedCrossRefGoogle Scholar
  3. Bolt HM. Metabolism of estrogens — natural and synthetic. Pharmacology and Therapeutics 4: 155–181, 1979PubMedCrossRefGoogle Scholar
  4. 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, 1975PubMedCrossRefGoogle Scholar
  5. Breuer H, Knuppen R. Enzymes of estrogen metabolism. In Clayton RB (Ed.) Methods in enzymology, Vol. 15, Steroids and terpenoids, Academic Press, New York, 1969Google Scholar
  6. Conney AH, Levin W, Jacobson M, Kuntzman R. Effects of drugs and environmental chemicals on steroid metabolism. Clinical Pharmacology and Therapeutics 14: 727–741, 1973PubMedGoogle Scholar
  7. Fishman J, Hellman L, Zumoff B, Cassouto J. Pathway and stereochemistry of the formation of estriols in man. Biochemistry 5: 1789–1794, 1966PubMedCrossRefGoogle Scholar
  8. Fishman J, Hellman L, Zumoff B, Gallagher TF. Effect of thyroid on hydroxylation of estrogens in man. Journal of Clinical Endocrinology 25: 365–368, 1965CrossRefGoogle Scholar
  9. 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, 1973PubMedCrossRefGoogle Scholar
  10. Gurpide E. Metabolic influences on the action of estrogens: therapeutic implications. Pediatrics 62 (Suppl.): 1114–1120, 1978PubMedGoogle Scholar
  11. 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, 1963Google Scholar
  12. 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, 1982PubMedCrossRefGoogle Scholar
  13. 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, 1967CrossRefGoogle Scholar
  14. Hembree WC, Bardin CW, Lipsett MB. A study of estrogen metabolic clearance rates and transfer factors. Journal of Clinical Investigation 48: 1809–1819, 1969PubMedCrossRefGoogle Scholar
  15. Horky K, Kuchel O, Starka L, Gregorova I. Effect of aminoglutethimide on extraglandular metabolism of exogenous testosterone. Metabolism 20: 331–336, 1971PubMedCrossRefGoogle Scholar
  16. 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, 1982PubMedGoogle Scholar
  17. Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis and Rheumatism 22: 1195–1198, 1979PubMedCrossRefGoogle Scholar
  18. 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, 1981PubMedCrossRefGoogle Scholar
  19. Lisboa BP, Diczfalusy E. Separation and characterisation of steroid oestrogens by means of thin-layer chromatography. Acta Endocrinologica 40: 60–81, 1962PubMedGoogle Scholar
  20. Longcope C. The metabolism of estrone sulfate in normal males. Journal of Clinical Endocrinology 34: 113–122, 1972CrossRefGoogle Scholar
  21. 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, 1981PubMedCrossRefGoogle Scholar
  22. 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, 1968PubMedCrossRefGoogle Scholar
  23. 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, 1974PubMedCrossRefGoogle Scholar
  24. 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, 1984aPubMedCrossRefGoogle Scholar
  25. Lønning PE, Kvinnsland S, Jahren G. Aminoglutethimide and warfarin: a new important drug interaction. Cancer Chemotherapy and Pharmacology 12: 10–12, 1984bPubMedCrossRefGoogle Scholar
  26. Lønning PE, Schanche JS, Kvinnsland S, Ueland PM. Single-dose and steady-state kinetics of aminoglutethimide. Clinical Pharmacokinetics 10: 353–364, 1985PubMedCrossRefGoogle Scholar
  27. 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, 1986PubMedCrossRefGoogle Scholar
  28. 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, 1976Google Scholar
  29. 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, 1979PubMedGoogle Scholar
  30. 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, 1984PubMedCrossRefGoogle Scholar
  31. 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, 1980PubMedCrossRefGoogle Scholar
  32. Nakamura Y, Ueda S. Induction of testosterone 16β-hydroxylase in rat liver microsomes by phenobarbital pretreatment. Biochemical and Biophysical Research Communications 93: 1014–1019, 1980PubMedCrossRefGoogle Scholar
  33. Notelovitz M, Tjapkes J, Ware M. Interaction between estrogen and dilantin in a menopausal woman. New England Journal of Medicine 304: 788, 1981PubMedCrossRefGoogle Scholar
  34. Roberts RK, Grice J, Wood L, Petroff V, McGuffie C. Cimetidine impairs the elimination of theophylline and antipyrine. Gastroenterology 81: 19–21, 1981PubMedGoogle Scholar
  35. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications, Lea and Febiger, Philadelphia, 1980Google Scholar
  36. Ruder HJ, Loriaux L, Lipsett MB. Estrone sulfate: production rate and metabolism in man. Journal of Clinical Investigation 51: 1020–1033, 1972PubMedCrossRefGoogle Scholar
  37. Samojlik E, Santen RJ, Worgul TJ. Plasma estrone sulfate assessment of reduced estrogen production during treatment of metastatic breast carcinoma. Steroids 39: 497–507, 1982PubMedCrossRefGoogle Scholar
  38. 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, 1980PubMedCrossRefGoogle Scholar
  39. 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, 1957PubMedCrossRefGoogle Scholar
  40. 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, 1981PubMedCrossRefGoogle Scholar
  41. 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, 1974PubMedCrossRefGoogle Scholar
  42. 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, 1980PubMedCrossRefGoogle Scholar
  43. 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, 1978PubMedCrossRefGoogle Scholar
  44. 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, 1977aPubMedCrossRefGoogle Scholar
  45. 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, 1977bPubMedCrossRefGoogle Scholar
  46. 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, 1984PubMedCrossRefGoogle Scholar
  47. 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, 1984PubMedCrossRefGoogle Scholar
  48. 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, 1980CrossRefGoogle Scholar
  49. 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, 1971CrossRefGoogle Scholar
  50. Støa KF, Skulstad PA. Biliary and urinary metabolites of intravenously and intraduodenally administered 17β-oestradiol and oestriol. Steroids and Lipids Research 3: 299–314, 1972PubMedGoogle Scholar
  51. Vermeulen A, Paridaens R, Heuson JC. Effects of aminoglutethimide on adrenal steroid secretion. Clinical Endocrinology 19: 673–682, 1983PubMedCrossRefGoogle Scholar
  52. 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, 1974PubMedCrossRefGoogle Scholar
  53. 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, 1986CrossRefGoogle Scholar
  54. 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, 1970PubMedGoogle Scholar
  55. Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390, 1975PubMedGoogle Scholar
  56. 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, 1968CrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • P. E. Lønning
    • 1
  • S. Kvinnsland
    • 1
  • T. Thorsen
    • 1
  • P. M. Ueland
    • 1
  1. 1.Departments of Biochemical Endocrinology, Oncology and Clinical Pharmacology Unit, Department of PharmacologyUniversity of BergenBergenNorway

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