Identification

Name
Aminoglutethimide
Accession Number
DB00357  (APRD00592)
Type
Small Molecule
Groups
Approved, Investigational
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
  • 2-(p-Aminophenyl)-2-ethylglutarimide
  • 3-Ethyl-3-(p-aminophenyl)-2,6-dioxopiperidine
  • Aminoglutethimid
  • Aminoglutéthimide
  • Aminoglutethimide
  • Aminoglutethimidum
  • Aminoglutetimida
  • Aminoglutetimide
  • DL-Aminoglutethimide
  • p-Aminoglutethimide
  • α-(p-Aminophenyl)-α-ethylglutarimide
External IDs
BA 16038 / C 16038-BA
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cytadren Tab 250mgTablet250 mgOralNovartis1983-12-311999-08-04Canada
International/Other Brands
Cytadren (Novartis) / Elipten (Ciba) / Mamomit (Pliva Hrvatska) / Orimeten (Novartis) / Rogluten (Actavis)
Categories
UNII
0O54ZQ14I9
CAS number
125-84-8
Weight
Average: 232.2783
Monoisotopic: 232.121177766
Chemical Formula
C13H16N2O2
InChI Key
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

Pharmacology

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.

Structured Indications
Not Available
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.

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.

TargetActionsOrganism
ACytochrome P450 19A1
inhibitor
Human
ACholesterol side-chain cleavage enzyme, mitochondrial
inhibitor
Human
Absorption

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

Volume of distribution
Not Available
Protein binding

21-25%

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 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

Clearance
Not Available
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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Aminoglutethimide.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
AripiprazoleThe serum concentration of Aripiprazole can be decreased when it is combined with Aminoglutethimide.Approved, Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Aminoglutethimide.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Aminoglutethimide.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Aminoglutethimide.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Aminoglutethimide.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Aminoglutethimide.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Aminoglutethimide.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Aminoglutethimide.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Aminoglutethimide.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
MethadoneThe serum concentration of Methadone can be increased when it is combined with Aminoglutethimide.Approved
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Aminoglutethimide.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Aminoglutethimide.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Aminoglutethimide.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Aminoglutethimide.Experimental
RilpivirineThe serum concentration of Rilpivirine can be decreased when it is combined with Aminoglutethimide.Approved
SaxagliptinThe serum concentration of Saxagliptin can be decreased when it is combined with Aminoglutethimide.Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Aminoglutethimide.Approved, Investigational
Food Interactions
  • Take without regard to meals.

References

Synthesis Reference

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

General References
Not Available
External Links
Human Metabolome Database
HMDB14501
KEGG Drug
D00574
KEGG Compound
C07617
PubChem Compound
2145
PubChem Substance
46506066
ChemSpider
2060
BindingDB
9460
ChEBI
2654
ChEMBL
CHEMBL488
Therapeutic Targets Database
DAP000842
PharmGKB
PA448375
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aminoglutethimide
ATC Codes
L02BG01 — Aminoglutethimide
FDA label
Download (122 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2TerminatedTreatmentProstate Cancer1
3CompletedTreatmentEarly-Stage Breast Cancer1

Pharmacoeconomics

Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
TabletOral250 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)223-225Hoffmann, 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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0ue9-5960000000-f9b33cb2d18e6b01ae76
Mass Spectrum (Electron Ionization)MSsplash10-0f89-3950000000-013571ce504af9a2d603
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0540-1970000000-fc41c032a79d79173387
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0540-2960000000-949d8dddc3981b8c3e63
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001j-3910000000-d92bbd37c74ab8b7828d

Taxonomy

Description
This compound belongs to the class of organic compounds known as aniline and substituted anilines. These are organic compounds containing an aminobenzene moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Aniline and substituted anilines
Direct Parent
Aniline and substituted anilines
Alternative Parents
Tetrahydropyridines / N-acylimines / Lactims / Amino acids and derivatives / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Primary amines / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
Aniline or substituted anilines / Tetrahydropyridine / Hydropyridine / Amino acid or derivatives / N-acylimine / Lactim / Organoheterocyclic compound / Organic 1,3-dipolar compound / Propargyl-type 1,3-dipolar organic compound / Carboxylic acid derivative
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
substituted aniline, dicarboximide, piperidones (CHEBI:2654) / a small molecule (CPD-10532)

Targets

Details
1. Cytochrome P450 19A1
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name
CYP19A1
Uniprot ID
P11511
Uniprot Name
Aromatase
Molecular Weight
57882.48 Da
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:17139284]
  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:17016423]
  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:16332571]
  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:16244789]
  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:16474421]
  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:17602675]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, nad(p)h as one donor, and incorporation of one atom of oxygen
Specific Function
Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.
Gene Name
CYP11A1
Uniprot ID
P05108
Uniprot Name
Cholesterol side-chain cleavage enzyme, mitochondrial
Molecular Weight
60101.87 Da
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:16817851]
  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:11161433]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy. 1981 Sep-Oct;1(2):95-120. [PubMed:6765487]
  2. Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH: Medical management of Cushing disease. Neurosurg Focus. 2007;23(3):E10. [PubMed:17961023]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy. 1981 Sep-Oct;1(2):95-120. [PubMed:6765487]
  2. Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH: Medical management of Cushing disease. Neurosurg Focus. 2007;23(3):E10. [PubMed:17961023]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy. 1981 Sep-Oct;1(2):95-120. [PubMed:6765487]
  2. Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH: Medical management of Cushing disease. Neurosurg Focus. 2007;23(3):E10. [PubMed:17961023]

Drug created on June 13, 2005 07:24 / Updated on November 07, 2017 01:36