Aminoglutethimide accelerates its own metabolism from a basal value of 2.6±0.3 (S.E.) liters/24 hours to 5.3±1.4 liters/24 hours after 1 to 2 weeks of Aminoglutethimide administration, and markedly accelerates the metabolism of the synthetic glucocorticoid and dexamethasone, from basal values of 145±26.6 liters/24 hours to 568±127 liters/24 hours (p < 0.02) after 2 weeks of Aminoglutethimide administration. Aminoglutethimide (150 mg/kg) abolishes the induction of ornithine decarboxylase (ODC) and almost depletes the gonads and plasma of progesterone or testosterone elicited by human chorionic gonadotropin (hCG) in the ovary of adult female mice and the testis of immature male mice, which is related to an inhibition of cAMP-dependent protein kinase (IC50 287 μM) rather than blockade of the steroidogenic pathway.

Absorption, Distribution and Excretion
Rapidly and completely absorbed from gastrointestinal tract. The bioavailability of tablets is equivalent to equal doses given as a solution.
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.
Cytadren is rapidly and completely absorbed after oral administration. In 6 healthy male volunteers, maximum plasma levels of Cytadren averaged 5.9 ug/mL at a medium of 1.5 hours after ingestion of 250 mg tablets. The bioavailability of tablets is equivalent to equal doses given as a solution.
Aminoglutethimide crosses the placenta ...
It is not known weather aminoglutethimide is distributed into breast milk.
After ingestion of a single oral dose, 34% to 54% is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as the N-acetyl derivative.
For more Absorption, Distribution and Excretion (Complete) data for AMINOGLUTETHIMIDE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.
Hepatic; the major metabolite is N-acetylaminoglutethimide; there may be genetic variation among individuals in the rate of acetylation.
Four ... metabolites of aminoglutethimide have been identified in the urine of patients being treated chronically with the drug. These were products of hydroxylation of the 3-ethylpiperidine-2,6-dione residue, namely 3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione and its acetylamino analog, 3-(4-aminophenyl)-3-(1-hydroxyethyl)piperidine-2,6-dione, and 3-(4-aminophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, the lactone formed by rearrangement of 3-(4-aminophenyl)-3-(2-hydroxyethyl)piperidine-2,6-dione. ... These new metabolites were minor constituents compared with aminoglutethimide and with the previously identified major metabolites 3-(4-acetylaminophenyl)-3-ethylpiperidine-2,6-dione and 3-(4-hydroxylaminophenyl)-3-ethylpiperidine-2,6-dione. There were marked species differences between rat and human inasmuch as almost all the metabolites in the urine of the rat were N-acetylated whereas most of the human metabolites were not. However, 5-hydroxylation of the piperidinedione residue was stereoselective in the same sense in both species, the cis isomer being formed exclusively. Synthetic cis-3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione did not inhibit the activity of the target enzyme systems desmolase and aromatase in vitro, and therefore, like other metabolites so far described, is an inactivation product of the drug.
Hydroxylaminoglutethimide (3-ethyl-3-(4-hydroxylaminophenyl)-2,6-piperidinedione) has been identified as a novel metabolite of aminoglutethimide (3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione) in the urine of patients treated chronically with this drug. The metabolite was isolated by reverse-phase thin-layer chromatography, and characterized by comparison of its mass spectrum and chromatographic properties with those of the synthetic compound. Hydroxylaminoglutethimide is unstable; it is readily oxidized to nitrosoglutethimide and disproportionates in the mass spectrometer into this compound and aminoglutethimide. In none of four patients studied was the metabolite detected in the urine after the first dose of the drug. In one patient it appeared after the second dose and in two more within seven to eight days suggesting that its formation is drug-induced, and that it may be the metabolite responsible for the diminished half-life of aminoglutethimide during chronic therapy. The profile of metabolites from one patient, examined by high-performance liquid chromatography after the first dose and again after six weeks of therapy afforded evidence that the formation of hydroxylaminoglutethimide was at the expense of a major metabolite N-acetylaminoglutethimide.
Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 hr urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily).
Extensive metabolism occurred in all species, with N-acetylaminoglutethimide being the major metabolite except for dog and man. In the latter two species unchanged drug was the main product excreted. A metabolite, 3-(4-acetamidophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, not previously found in human urine, was identified. Chronic administration of aminoglutethimide to rats produced no detectable change in the excretory or metabolite patterns of the drug. However chronic administration of phenobarbitone decreased the urinary excretion of (14)C over a 72 hr period. Residual (72 hr) tissue levels of (14)C were less than 1 microgram equivalent of (14)C-aminoglutethimide/g tissue in the rat, guinea-pig and rabbit. Dog tissues retained a considerable quantity of (14)C at this time.
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.
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.
Half Life: 12.5 ± 1.6 hours

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Biological Half-Life
12.5 ± 1.6 hours
12.5 hours; reduced to 7 hours after prolonged (2 to 32 weeks) treatment because aminoglutethimide induces hepatic enzymes and accelerates its own metabolism.

Toxicity Summary
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.

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Protein Binding
21-25%

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Toxicity Data
Oral LD50s (mg/kg): rats, 1800; dogs, >100. Intravenous LD50s (mg/kg): rats, 156; dogs, >100.

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Interactions
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.

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Non-Human Toxicity Values
LD50 Mouse ip 625 mg/kg

Eur J Med Chem.2009 Oct;44(10):4121-7;Cancer Res.1982 Aug;42(8 Suppl):3353s-3359s.

Therapeutic Uses
Adrenocortical suppressant; antineoplastic
Aminoglutethimide is indicated for temporary suppression of adrenal function in selected patients with Cushing's syndrome including that associated withadrenal carcinoma and etopic adrenocorticotropic hormone (ACTH)-producing tumors or adrenal hyperplasia. /Included in US product label/
Aminoglutethimide is indicated to produce a "pharmacologic adrenalectomy" in the treatment of post menopausal metastatic breast cancer, especially inoperable or recurrent breast cancer proven to be hormone dependent, but resistant to therapy with tamoxifen. /Included in US product label/
Aminoglutethimide is indicated for treatment of prostatic carcinoma unresponsive to hormonal or surgical therapy. /Included in US product label/
For more Therapeutic Uses (Complete) data for AMINOGLUTETHIMIDE (7 total), please visit the HSDB record page.

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Drug Warnings
Cytadren may cause adrenocortical hypofunction, especially under conditions of stress, such as surgery, trauma, or acute illness. Patients should be carefully monitored and given hydrocortisone and mineralocorticoid supplements as indicated. Dexamethasone should not be used.
Cytadren may also suppress aldosterone production by the adrenal cortex and may cause orthostatic or persistent hypotension. The blood pressure should be monitored in all patients at appropriate intervals. Patients should be advised of the possible occurrence of weakness and dizziness as symptoms of hypotension, and measures to be taken should they occur.
Cytadren can cause fetal harm when administered to a pregnant woman. In the earlier experience with the drug in about 5000 patients, two cases of pseudohermaphroditism were reported in female infants whose mothers were treated with Cytadren ... If this drug must be used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.
Patients should be warned that drowsiness may occur and that they should not drive, operate potentially dangerous machinery, or engage in other activities that may become hazardous because of decreased alertness.
For more Drug Warnings (Complete) data for AMINOGLUTETHIMIDE (19 total), please visit the HSDB record page.

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

C13H16N2O2

232.28

232.121

125-84-8

2145

White to off-white solid powder

1.2±0.1 g/cm3

457.4±45.0 °C at 760 mmHg

152-154 °C(lit.)

230.4±28.7 °C

0.0±1.1 mmHg at 25°C

1.566

1.41

2

3

2

17

321

0

ROBVIMPUHSLWNV-UHFFFAOYSA-N

InChI=1S/C13H16N2O2/c1-2-13(8-7-11(16)15-12(13)17)9-3-5-10(14)6-4-9/h3-6H,2,7-8,14H2,1H3,(H,15,16,17)

3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 8 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)