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Identification
NameAminoglutethimide
Accession NumberDB00357  (APRD00592)
TypeSmall Molecule
GroupsApproved
Description

An aromatase inhibitor that produces a state of “medical” adrenalectomy by blocking the production of adrenal steroids. It also blocks the conversion of androgens to estrogens. Aminoglutethimide has been used in the treatment of advanced breast and prostate cancer. It was formerly used for its weak anticonvulsant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p454)

Structure
Thumb
Synonyms
SynonymLanguageCode
2-(p-Aminophenyl)-2-ethylglutarimideNot AvailableWHO
3-Ethyl-3-(P-aminophenyl)-2,6-dioxopiperidineNot AvailableNot Available
alpha-(P-Aminophenyl)-alpha-ethylglutarimideNot AvailableNot Available
AminoglutethimidGermanPh. Eur. 7
AminoglutéthimideFrenchDCF
AminoglutethimideNot AvailableBP 2011, Ph. Eur. 7, USP 34
AminoglutethimidumLatinINN
AminoglutetimidaSpanishINN
AminoglutetimideNot AvailableDCIT
Dl-AminoglutethimideNot AvailableNot Available
EliptenNot AvailableIS
P-AminoglutethimideNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
CytadrenNovartis
MamomitPliva Hrvatska
OrimetenNovartis
RoglutenActavis
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number125-84-8
WeightAverage: 232.2783
Monoisotopic: 232.121177766
Chemical FormulaC13H16N2O2
InChI KeyROBVIMPUHSLWNV-UHFFFAOYSA-N
InChI
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)
IUPAC Name
3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione
SMILES
CCC1(CCC(=O)NC1=O)C1=CC=C(N)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPiperidines
Sub ClassPhenylpiperidines
Direct ParentPhenylpiperidines
Alternative Parents
Substituents
  • Phenylpiperidine
  • Substituted aniline
  • Piperidinedione
  • Piperidinone
  • Dicarboximide
  • Delta-lactam
  • Aniline
  • Benzenoid
  • Primary aromatic amine
  • Monocyclic benzene moiety
  • Carboxylic acid imide, n-unsubstituted
  • Carboxylic acid imide
  • Lactam
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsAminoglutethimide 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 actionAminoglutethimide 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.
AbsorptionRapidly and completely absorbed from gastrointestinal tract. The bioavailability of tablets is equivalent to equal doses given as a solution.
Volume of distributionNot Available
Protein binding21-25%
Metabolism

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 eliminationAfter 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 life12.5 ± 1.6 hours
ClearanceNot Available
ToxicityOral 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.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9811
Blood Brain Barrier+0.9908
Caco-2 permeable+0.5
P-glycoprotein substrateSubstrate0.7352
P-glycoprotein inhibitor INon-inhibitor0.7439
P-glycoprotein inhibitor IINon-inhibitor0.9432
Renal organic cation transporterNon-inhibitor0.8514
CYP450 2C9 substrateNon-substrate0.8342
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5505
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.923
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8682
Ames testNon AMES toxic0.8016
CarcinogenicityNon-carcinogens0.8401
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7219 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.99
hERG inhibition (predictor II)Non-inhibitor0.6295
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point223-225Hoffmann, K.and Urech, E.; U.S. Patent 2848,455; August 19,1958; assigned to Ciba Pharmaceutical Products, Inc.
water solubilityPractically insoluble in waterNot Available
logP1.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.371 mg/mLALOGPS
logP1.49ALOGPS
logP1.3ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)11.69ChemAxon
pKa (Strongest Basic)4.28ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area72.19 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity65.35 m3·mol-1ChemAxon
Polarizability24.69 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraMS
References
Synthesis Reference

Hoffmann, K.and Urech, E.; U.S. Patent 2,848,455; August 19,1958; assigned to Ciba Pharmaceutical Products, Inc.

General ReferenceNot Available
External Links
ATC CodesL02BG01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (122 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcenocoumarolMay increase the metabolism of Vitamin K Antagonists.
AminophyllineMay increase the metabolism of Theophylline Derivatives.
CorticotropinMay increase the metabolism of Corticosteroids (Systemic).
Cortisone acetateMay increase the metabolism of Corticosteroids (Systemic).
Cyproterone acetateMay increase the metabolism of Progestins.
DesogestrelMay increase the metabolism of Progestins.
DrospirenoneMay increase the metabolism of Progestins.
Ethinyl EstradiolMay increase the metabolism of Progestins.
EthynodiolMay increase the metabolism of Progestins.
EtonogestrelMay increase the metabolism of Progestins.
FludrocortisoneMay increase the metabolism of Corticosteroids (Systemic).
LevonorgestrelMay increase the metabolism of Progestins.
Medroxyprogesterone AcetateMay increase the metabolism of Progestins.
Megestrol acetateMay increase the metabolism of Progestins.
MestranolMay increase the metabolism of Progestins.
MethadoneMay increase the serum concentration of Methadone.
MethylprednisoloneMay increase the metabolism of Corticosteroids (Systemic).
NorelgestrominMay increase the metabolism of Progestins.
NorethindroneMay increase the metabolism of Progestins.
NorgestimateMay increase the metabolism of Progestins.
PrednisoneMay increase the metabolism of Corticosteroids (Systemic).
ProgesteroneMay increase the metabolism of Progestins.
TamoxifenMay increase the metabolism of Tamoxifen.
TheophyllineMay increase the metabolism of Theophylline Derivatives.
Food Interactions
  • Take without regard to meals.

Targets

1. Cytochrome P450 19A1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 19A1 P11511 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Greco F, Vicent MJ, Penning NA, Nicholson RI, Duncan R: HPMA copolymer-aminoglutethimide conjugates inhibit aromatase in MCF-7 cell lines. J Drug Target. 2005 Sep-Nov;13(8-9):459-70. Pubmed
  4. Martinez-Campa C, Gonzalez A, Mediavilla MD, Alonso-Gonzalez C, Sanchez-Barcelo EJ, Cos S: Melatonin enhances the inhibitory effect of aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells. Breast Cancer Res Treat. 2005 Dec;94(3):249-54. Epub 2005 Oct 22. Pubmed
  5. Shirakawa H, Katsuki H, Kume T, Kaneko S, Akaike A: Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons. Br J Pharmacol. 2006 Apr;147(7):729-36. Pubmed
  6. Siraki AG, Bonini MG, Jiang J, Ehrenshaft M, Mason RP: Aminoglutethimide-induced protein free radical formation on myeloperoxidase: a potential mechanism of agranulocytosis. Chem Res Toxicol. 2007 Jul;20(7):1038-45. Epub 2007 Jun 30. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Cholesterol side-chain cleavage enzyme, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cholesterol side-chain cleavage enzyme, mitochondrial P05108 Details

References:

  1. Slominski A, Semak I, Wortsman J, Zjawiony J, Li W, Zbytek B, Tuckey RC: An alternative pathway of vitamin D metabolism. Cytochrome P450scc (CYP11A1)-mediated conversion to 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2. FEBS J. 2006 Jul;273(13):2891-901. Pubmed
  2. Oka H, Emori Y, Hayashi Y, Nomoto K: Breakdown of Th cell immune responses and steroidogenic CYP11A1 expression in CD4+ T cells in a murine model implanted with B16 melanoma. Cell Immunol. 2000 Nov 25;206(1):7-15. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy. 1981 Sep-Oct;1(2):95-120. Pubmed
  1. BA Gross, SA Mindea, AJ Pick, JP Chandler, Batjer HH: Medical management of Cushing disease. Neurosurgical Focus. 2007 Sep;23(3).

2. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy. 1981 Sep-Oct;1(2):95-120. Pubmed
  1. BA Gross, SA Mindea, AJ Pick, JP Chandler, Batjer HH: Medical management of Cushing disease. Neurosurgical Focus. 2007 Sep;23(3).

3. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy. 1981 Sep-Oct;1(2):95-120. Pubmed
  1. BA Gross, SA Mindea, AJ Pick, JP Chandler, Batjer HH: Medical management of Cushing disease. Neurosurgical Focus. 2007 Sep;23(3).

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Drug created on June 13, 2005 07:24 / Updated on March 27, 2014 14:32