Aminoglutethimide

Aminoglutethimide may inhibit the adrenal response to ACTH; this may interfere with the therapeutic response to ACTH.

/Upon concomitant administration of/ CNS depression-producing medications, additive CNS depression may occur.

Hyponatremia may occur /with concomitant administration of/ diuretics.

Cytadren accelerates the metabolism of dexamethasone...

For more Interactions (Complete) data for AMINOGLUTETHIMIDE (12 total), please visit the HSDB record page.

Aminoglutethimide reduces the production of D5-pregnenolone and 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 aminoglutethimide to cytochrome P-450 complexes. Specifically, the drug binds to and inhibits aromatase which is essential for the generation of estrogens from androstenedione and testosterone. 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 aminoglutethimide. The compensatory increase in ACTH secretion can be suppressed by the simultaneous administration of hydrocortisone. Since aminoglutethimide increases the rate of metabolism of dexamethasone but not that of hydrocortisone, the latter is preferred as the adrenal glucocorticoid replacement. Although aminoglutethimide 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 aminoglutethimide. In spite of an increase in TSH, aminoglutethimide has not been associated with increased prolactin secretion.

/HUMAN EXPOSURE STUDIES/ Marked leukopenia and/or thrombocytopenia occurred in 12 of 1333 patients treated with aminoglutethimide (0.9% incidence). Depression of blood cell counts was evident within 7 weeks of starting treatment. No delayed toxicity was encountered. Blood cell counts recovered promptly upon cessation of aminoglutethimide in all but one patient, who died from septicemia and marrow aplasia.

/SIGNS AND SYMPTOMS/ An acute overdose with Cytadren may reduce the production of steroids in the adrenal cortex to a degree that is clinically relevant. The following manifestations may be expected: Respiratory depression, hypoventilation; hypotension, hypovolemic shock due to dehydration; somnolence, lethargy, coma, ataxia, dizziness, fatigue; nausea, vomiting; loss of sodium and water; hyponatremia, hypochloremia, hyperkalemia, hypoglycemia. The signs and symptoms of acute overdosage with Cytadren may be aggravated or modified if alcohol, hypnotics, tranquilizers, or tricyclic antidepressants have been taken at the same time.

/CASE REPORTS/ A patient with advanced breast cancer who died of septicemia associated with aminoglutethimide induced agranulocytosis, is reported. Aminoglutethimide is effective and widely used in the treatment of metastatic adenocarcinoma of breast. Thrombocytopenia, leukopenia, or pancytopenia have been reported as complications of therapy in 1.6% of 1345 patients treated in recently published clinical trials employing aminoglutethimide; and this may underestimate the true incidence of this drug side effect.

/CASE REPORTS/ A 67-year-old patient with breast carcinoma on treatment with aminoglutethimide (AG) developed profound leukopenia and sepsis. WBC count recovered within 1 week and the drug was renewed without further complications. The hematological toxicity of AG is reviewed. Detailed descriptions of this side effect of AG are usually lacking in most published series. It appears though that blood dyscrasia due to AG occurs rarely and is promptly reversible upon discontinuation of the drug, but renewal of its administration is not always possible.

/OTHER TOXICITY INFORMATION/ Aminoglutethimide crosses the placenta and has been shown to cause pseudohermaphroditism in female infants whose mothers took concommitant anticonvulsants.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

aminoglutethimide

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The aromatase inhibitor, aminoglutethimide, causes a blood dyscrasia in about 1% of women taking the drug for the treatment of advanced breast cancer. The parent compound, glutethimide, is known not to possess this toxic action. The effect of both drugs on bone (femur) marrow cells of mice and rats was examined ... For the in vivo study, glutethimide and aminoglutethimide were given orally (50 mg/kg, daily). After 3 wk of this regimen in mice, there was a significant fall (about 50%) in both white blood cell and platelet counts. This is similar to the blood picture changes induced by aminoglutethimide in women. No hematological effects were observed in rats receiving this drug and glutethimide was without effect in either species.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats given doses of 10 to 60 mg per kg of bodyweight per day (mg/kg/day) developed benign and malignant tumors of the adrenal cortex, ovaries, thyroid, and urinary bladder.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Aminoglutethimide has been shown to cause increased incidence of fetal death and teratogenic effects, including pseudohermaphroditism, in rats given up to three times the highest recommended human dose.[Thomson.Micromedex. Drug Information for the Health Care Professional. 25th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2005., p. 91]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in female rats at doses equivalent to 0.5 and 1.25 times the maximum daily human dose found a decrease in fetal implantation.[Thomson.Micromedex. Drug Information for the Health Care Professional. 25th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2005., p. 91]

For more Non-Human Toxicity Excerpts (Complete) data for AMINOGLUTETHIMIDE (8 total), please visit the HSDB record page.

Symptomatic treatment of overdosage is recommended. Since aminoglutethimide and glutethimide are chemically related, measures that have been used in successfully removing glutethimide from the body might be useful in removing aminoglutethimide. ...Close monitoring should be provided, and appropriate measures taken to support vital functions, if necessary. If deficiency of circulating glucocorticoids develops, intravenous infusion of a soluble hydrocortisone preparation ... and glucose solution should be given within 3 hours. After initial infusion is complete, an intravenous administration of hydrocortisone, ... should be continued until the patient is able to take oral cortisone. If hypovolemia or hypotension occurs, an intravenous administration of norepinephrine ... in isotonic sodium chloride should be administered according to the patient's needs and response. After rehydration ... plasma or blood should be given for maintenance of sufficient circulatory volume. Dialysis may be considered in severe intoxication.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl aminoglutethimide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

THERAP CAT: Adrenocorticol supressant; antineoplastic

Treatment of Cushing's syndrome

For the suppression of adrenal function in selected patients with Cushing's syndrome, malignant neoplasm of the female breast, and carcinoma in situ of the breast.