Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1984 Oct;18(4):495–505. doi: 10.1111/j.1365-2125.1984.tb02497.x

The effect of acetylator phenotype on the disposition of aminoglutethimide.

A M Adam, H J Rogers, S A Amiel, R D Rubens
PMCID: PMC1463619  PMID: 6487491

Abstract

Aminoglutethimide (AG) 500 mg was administered orally to four normal volunteers and eight patients undergoing treatment for metastatic breast cancer. In each subject the acetylator phenotype was established from the monoacetyldapsone (MADDS)/dapsone (DDS) ratio. Acetylaminoglutethimide (acetylAG) rapidly appeared in the plasma and its disposition paralleled that of AG. A close relationship (P less than 0.01) was observed between the acetyl AG/AG and MADDS/DDS ratio suggesting that AG may undergo polymorphic acetylation like DDS. AG half-life was 19.5 +/- 7.7 h in seven fast acetylators of DDS and 12.6 +/- 2.3 h in five slow acetylators and its apparent metabolic clearance was significantly (P less than 0.01) related to the acetylAG/AG ratio. Over 48 h the fast acetylators excreted 7.7 +/- 4.4% of the administered AG dose in the urine as unchanged AG as compared to 12.4 +/- 2.8% in slow acetylators. A much smaller fraction of the dose was excreted as acetylAG: 3.6 +/- 1.5% by fast and 1.9 +/- 1.0% by slow acetylators respectively. After 7 days treatment with AG at an accepted clinical dose regimen to the eight patients there were significant reductions in the half-lives of AG (P less than 0.01) and acetylAG (P less than 0.01) and a trend (0.1 greater than P greater than 0.05) towards reduction of the acetylAG/AG ratio which became significant (P less than 0.05) if the one patient on a known enzyme inducer was omitted. The mean apparent volume of distribution was not significantly (P greater than 0.1) altered but the mean apparent systemic clearance of AG was increased (P less than 0.05). These changes are attributed to auto-induction of oxidative enzymes involved in AG metabolism.

Full text

PDF
495

Selected References

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

  1. Caddy B., Stead A. H., Johnstone E. C. The urinary excretion of phenelzine. Br J Clin Pharmacol. 1978 Aug;6(2):185–188. doi: 10.1111/j.1365-2125.1978.tb00853.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Carr K., Oates J. A., Nies A. S., Woosley R. L. Simultaneous analysis of dapsone and monoacetyldapsone employing high performance liquid chromatography: a rapid method for determination of acetylator phenotype. Br J Clin Pharmacol. 1978 Nov;6(5):421–427. doi: 10.1111/j.1365-2125.1978.tb04606.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cash R., Brough A. J., Cohen M. N., Satoh P. S. Aminoglutethimide (Elipten-Ciba) as an inhibitor of adrenal steroidogenesis: mechanism of action and therapeutic trial. J Clin Endocrinol Metab. 1967 Sep;27(9):1239–1248. doi: 10.1210/jcem-27-9-1239. [DOI] [PubMed] [Google Scholar]
  4. Coombes R. C., Foster A. B., Harland S. J., Jarman M., Nice E. C. Polymorphically acetylated aminoglutethimide in humans. Br J Cancer. 1982 Sep;46(3):340–345. doi: 10.1038/bjc.1982.209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Douglas J. S., Nicholls P. J. The partial fate of aminoglutethimide in man. J Pharm Pharmacol. 1972 Dec;24(Suppl):150P–150P. [PubMed] [Google Scholar]
  6. EVANS D. A., WHITE T. A. HUMAN ACETYLATION POLYMORPHISM. J Lab Clin Med. 1964 Mar;63:394–403. [PubMed] [Google Scholar]
  7. Fishman L. M., Liddle G. W., Island D. P., Fleischer N., Küchel O. Effects of amino-glutethimide on adrenal function in man. J Clin Endocrinol Metab. 1967 Apr;27(4):481–490. doi: 10.1210/jcem-27-4-481. [DOI] [PubMed] [Google Scholar]
  8. Foster A. B., Jarman M., Leung C. S., Rowlands M. G., Taylor G. N. Analogues of aminoglutethimide: selective inhibition of cholesterol side-chain cleavage. J Med Chem. 1983 Jan;26(1):50–54. doi: 10.1021/jm00355a011. [DOI] [PubMed] [Google Scholar]
  9. Gelber R., Peters J. H., Gordon G. R., Glazko A. J., Levy L. The polymorphic acetylation of dapsone in man. Clin Pharmacol Ther. 1971 Mar-Apr;12(2):225–238. doi: 10.1002/cpt1971122part1225. [DOI] [PubMed] [Google Scholar]
  10. Holmes D. G., Bogers W. A., Wideroe T. E., Huunan-Seppala A., Wideroe B. Endralazine, a new peripheral vasodilator: absence of effect of acetylator status on antihypertensive effect. Lancet. 1983 Mar 26;1(8326 Pt 1):670–671. doi: 10.1016/s0140-6736(83)91967-0. [DOI] [PubMed] [Google Scholar]
  11. Jackson L., Homeida M., Roberts C. J. The features of hepatic enzyme induction with glutethimide in man. Br J Clin Pharmacol. 1978 Dec;6(6):525–528. doi: 10.1111/j.1365-2125.1978.tb00877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jarman M., Foster A. B., Goss P. E., Griggs L. J., Howe I., Coombes R. C. Metabolism of aminoglutethimide in humans: identification of hydroxylaminoglutethimide as an induced metabolite. Biomed Mass Spectrom. 1983 Nov;10(11):620–625. doi: 10.1002/bms.1200101108. [DOI] [PubMed] [Google Scholar]
  13. Meredith P. A., Elliott H. L., McSharry D. R., Kelman A. W., Reid J. L. The pharmacokinetics of endralazine in essential hypertensives and in normotensive subjects. Br J Clin Pharmacol. 1983 Jul;16(1):27–32. doi: 10.1111/j.1365-2125.1983.tb02139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Murray F. T., Santner S., Samojlik E., Santen R. J. Serum aminoglutethimide levels: studies of serum half-life, clearance, and patient compliance. J Clin Pharmacol. 1979 Nov-Dec;19(11-12):704–711. doi: 10.1002/j.1552-4604.1979.tb01640.x. [DOI] [PubMed] [Google Scholar]
  15. Reece P. A., Cozamanis I., Zacest R. Influence of acetylator phenotype on the pharmacokinetics of a new vasodilator antihypertensive, endralazine. Eur J Clin Pharmacol. 1982;23(6):523–527. doi: 10.1007/BF00637500. [DOI] [PubMed] [Google Scholar]
  16. Reece P. A., Cozamanis I., Zacest R. Kinetics of hydralazine and its main metabolites in slow and fast acetylators. Clin Pharmacol Ther. 1980 Dec;28(6):769–778. doi: 10.1038/clpt.1980.234. [DOI] [PubMed] [Google Scholar]
  17. Santen R. J., Santner S. J., Tilsen-Mallett N., Rosen H. R., Samojlik E., Veldhuis J. D. In vivo and in vitro pharmacological studies of aminoglutethimide as an aromatase inhibitor. Cancer Res. 1982 Aug;42(8 Suppl):3353s–3359s. [PubMed] [Google Scholar]
  18. Santen R. J., Worgul T. J., Lipton A., Harvey H., Boucher A., Samojlik E., Wells S. A. Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med. 1982 Jan;96(1):94–101. doi: 10.7326/0003-4819-96-1-94. [DOI] [PubMed] [Google Scholar]
  19. Thompson T. A., Vermeulen J. D., Wagner W. E., Jr, Le Sher A. R. Aminoglutethimide bioavailability, pharmacokinetics, and binding to blood constituents. J Pharm Sci. 1981 Sep;70(9):1040–1043. doi: 10.1002/jps.2600700919. [DOI] [PubMed] [Google Scholar]
  20. Weber W. W., Hein D. W. Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet. 1979 Nov-Dec;4(6):401–422. doi: 10.2165/00003088-197904060-00001. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES