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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
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
SaltsNot Available
Brand names
NameCompany
CytadrenNovartis
MamomitPliva Hrvatska
OrimetenNovartis
RoglutenActavis
Brand mixturesNot Available
Categories
CAS number125-84-8
WeightAverage: 232.2783
Monoisotopic: 232.121177766
Chemical FormulaC13H16N2O2
InChI KeyInChIKey=ROBVIMPUHSLWNV-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPiperidines
SubclassPhenylpiperidines
Direct parentPhenylpiperidines
Alternative parentsPiperidinediones; Anilines; Delta Lactams; Primary Aromatic Amines; N-unsubstituted Carboxylic Acid Imides; Secondary Carboxylic Acid Amides; Carboxylic Acids; Polyamines
Substituentspiperidinedione; delta-lactam; aniline; piperidinone; benzene; primary aromatic amine; carboxylic acid imide, n-unsubstituted; carboxylic acid imide; lactam; carboxamide group; secondary carboxylic acid amide; polyamine; carboxylic acid derivative; carboxylic acid; amine; primary amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
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
Property Value Probability
Human Intestinal Absorption + 0.9811
Blood Brain Barrier + 0.9908
Caco-2 permeable + 0.5
P-glycoprotein substrate Substrate 0.7352
P-glycoprotein inhibitor I Non-inhibitor 0.7439
P-glycoprotein inhibitor II Non-inhibitor 0.9432
Renal organic cation transporter Non-inhibitor 0.8514
CYP450 2C9 substrate Non-substrate 0.8342
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.5505
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.923
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8682
Ames test Non AMES toxic 0.8016
Carcinogenicity Non-carcinogens 0.8401
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.7219 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.99
hERG inhibition (predictor II) Non-inhibitor 0.6295
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
TabletOral250 mg
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 solubility3.71e-01 g/lALOGPS
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 area72.19ChemAxon
rotatable bond count2ChemAxon
refractivity65.35ChemAxon
polarizability24.69ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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
ResourceLink
KEGG DrugD00574
KEGG CompoundC07617
PubChem Compound2145
PubChem Substance46506066
ChemSpider2060
BindingDB9460
ChEBI2654
ChEMBLCHEMBL488
Therapeutic Targets DatabaseDAP000842
PharmGKBPA448375
Drug Product Database587729
RxListhttp://www.rxlist.com/cgi/generic3/cytadren.htm
Drugs.comhttp://www.drugs.com/cdi/aminoglutethimide.html
WikipediaAminoglutethimide
ATC CodesL02BG01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(122 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcenocoumarolAminoglutethimide may decrease the anticoagulant effect of acenocoumarol.
AnisindioneAminoglutethimide may decrease the anticoagulant effect of anisindione.
DexamethasoneAminoglutethimide may decrease the effect of dexamethasone.
DicoumarolAminoglutethimide may decrease the anticoagulant effect of dicumarol.
TamoxifenAminoglutethimide 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.
TelithromycinAminoglutethimide may decrease the plasma concentration of Telithromycin. Consider alternate therapy.
TemsirolimusAminoglutethimide may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
TramadolAminoglutethimide may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
TrazodoneThe 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.
WarfarinAminoglutethimide 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.
Food Interactions
  • Take without regard to meals.

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

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).

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