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 Aminoglutethimide

Aminoglutethimide is an anti-steroid drug marketed under the tradename Cytadren by Novartis around the world. It blocks the production of steroids derived from cholesterol and is clinically used in the treatment of Cushing's syndrome and metastatic breast cancer. It is also a drug of abuse by body builders.

Cytadren inhibits the enzymatic conversion of cholesterol to Δ5-pregnenolone, resulting in a decrease in the production of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens. Cytadren blocks several other steps in steroid synthesis, including the C-11, C-18, and C-21 hydroxylations and the hydroxylations required for the aromatization of androgens to estrogens, mediated through the binding of Cytadren to cytochrome P-450 complexes. A decrease in adrenal secretion of cortisol is followed by an increased secretion of pituitary adrenocorticotropic hormone (ACTH), which will overcome the blockade of adrenocortical steroid synthesis by Cytadren. The compensatory increase in ACTH secretion can be suppressed by the simultaneous administration of hydrocortisone. Since Cytadren increases the rate of metabolism of dexamethasone but not that of hydrocortisone, the latter is preferred as the adrenal glucocorticoid replacement.

Although Cytadren inhibits the synthesis of thyroxine by the thyroid gland, the compensatory increase in thyroid-stimulating hormone (TSH) is frequently of sufficient magnitude to overcome the inhibition of thyroid synthesis due to Cytadren. In spite of an increase in TSH, Cytadren has not been associated with increased prolactin secretion.

Note: Cytadren was marketed previously as an anticonvulsant but was withdrawn from marketing for that indication in 1966 because of the effects on the adrenal gland.

Aminoglutethimide is indicated in conjunction with other drugs for the suppression of adrenal function in patients with Cushing's syndrome. It is also a 2nd or 3rd line choice for the treatment of hormone sensitive (estrogen and progesterone) metastatic breast cancer.

Cytadren, aminoglutethimide tablets USP, is an inhibitor of adrenocortical steroid synthesis, available as 250-mg tablets for oral administration. Its chemical name is 3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione.  Aminoglutethimide USP is a fine, white or creamy white, crystalline powder. It is very slightly soluble in water, and readily soluble in most organic solvents. It forms water- soluble salts with strong acids. Its molecular weight is 232.28. Inactive Ingredients. Cellulose compounds, colloidal silicon dioxide, starch, stearic acid, and talc.

Aminoglutethimide is abused by body builders and other steroid users to lower circulating levels of cortisol in the body and prevent muscle loss. Cortisol is catabolic to protein in muscle and effective blockade of P450scc by aminogluthethimide at high doses prevents muscle loss.

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67: Chester JA, Cunningham CL. Modulation of corticosterone does not affect the acquisition or expression of ethanol-induced conditioned place preference in DBA/2J mice. Pharmacol Biochem Behav. 1998 Jan;59(1):67-75. PubMed PMID: 9443538.

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70: Harvey HA. Issues concerning the role of chemotherapy and hormonal therapy of bone metastases from breast carcinoma. Cancer. 1997 Oct 15;80(8 Suppl):1646-51. Review. PubMed PMID: 9362431.

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72: Dowsett M. Aromatase inhibitors come of age. Ann Oncol. 1997 Jul;8(7):631-2. PubMed PMID: 9296213.

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78: Small EJ, Vogelzang NJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol. 1997 Jan;15(1):382-8. Review. PubMed PMID: 8996165.

79: Wiseman LR, Goa KL. Formestane. A review of its pharmacological properties and clinical efficacy in the treatment of postmenopausal breast cancer. Drugs Aging. 1996 Oct;9(4):292-306. Review. PubMed PMID: 8894526.

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98: Manni A. Clinical use of aromatase inhibitors in the treatment of breast cancers. J Cell Biochem Suppl. 1993;17G:242-6. Review. PubMed PMID: 8007705.

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