indication

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.

pharmacology

Aminoglutethimide inhibits the enzymatic conversion of cholesterol to D5-pregnenolone, resulting in a decrease in the production of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens.

mechanism of action

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.

toxicity

Oral LD50s (mg/kg): rats, 1800; dogs, >100. Intravenous LD50s (mg/kg): rats, 156; dogs, >100. Symptoms of overdose include respiratory depression, hypoventilation, hypotension, hypovolemic shock due to dehydration, somnolence, lethargy, coma, ataxia, dizziness, fatigue, nausea, and vomiting.

biotransformation

Hepatic. 34-54% of the administered dose is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as an N-acetyl derivative.

absorption

Rapidly and completely absorbed from gastrointestinal tract. The bioavailability of tablets is equivalent to equal doses given as a solution.

half life

12.5 ± 1.6 hours

route of elimination

After ingestion of a single oral dose, 34%-54% is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as the N-acetyl derivative.

drug interactions

Acenocoumarol: Aminoglutethimide may decrease the anticoagulant effect of acenocoumarol.

Anisindione: Aminoglutethimide may decrease the anticoagulant effect of anisindione.

Dexamethasone: Aminoglutethimide may decrease the effect of dexamethasone.

Dicumarol: Aminoglutethimide may decrease the anticoagulant effect of dicumarol.

Tamoxifen: Aminoglutethimide may increase Tamoxifen clearance decreasing its therapeutic effect. Consider alternate therapy or monitor for changes in Tamoxifen effects when Aminoglutethimide is initiated, discontinued or dose changed.

Telithromycin: Aminoglutethimide may decrease the plasma concentration of Telithromycin. Consider alternate therapy.

Temsirolimus: Aminoglutethimide may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Tramadol: Aminoglutethimide may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inducer, Aminoglutethimide, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Aminoglutethimide is initiated, discontinued or dose changed.

Warfarin: Aminoglutethimide may decrease the anticoagulant effect of warfarin by increasing its metabolism. Monitor for changes in prothrombin time and therapeutic effects of warfarin if aminoglutethimide is initiated, discontinued or dose changed.