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targets (2) enzymes (3)
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Identification
Name Aminoglutethimide
Accession Number DB00357 (APRD00592)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Dl-Aminoglutethimide
P-Aminoglutethimide
Salts Not Available
Brand names
Name Company
Cytadren
Elipten
Orimeten
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Adrenergic Agents
  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
CAS number 125-84-8
Weight Average: 232.2783
Monoisotopic: 232.121177766
Chemical Formula C13H16N2O2
InChI Key InChIKey=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)
Plain Text
IUPAC Name
3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione
SMILES
CCC1(CCC(=O)NC1=O)C1=CC=C(N)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Delta Lactams
  • Phenylpiperidines
Substructures
  • Carbonyl Compounds
  • Delta Lactams
  • Carboxylic Acids and Derivatives
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Phenylpiperidines
  • Piperidines
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Anilines
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.
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.
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
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Tablet Oral 250 mg
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 149.5 °C PhysProp
water solubility Practically insoluble in water Not Available
logP 1.3 Not Available
Predicted Properties
Property Value Source
water solubility 3.71e-01 g/l ALOGPS
logP 1.49 ALOGPS
logP 1.3 ChemAxon
logS -2.8 ALOGPS
pKa (strongest acidic) 11.69 ChemAxon
pKa (strongest basic) 4.28 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 72.19 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 65.35 ChemAxon
polarizability 24.69 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00574 Link_out
KEGG Compound C07617 Link_out
PubChem Compound 2145 Link_out
PubChem Substance 46506066 Link_out
ChemSpider 2060 Link_out
BindingDB 9460 Link_out
ChEBI 2654 Link_out
ChEMBL 2654 Link_out
Therapeutic Targets Database DAP000842 Link_out
PharmGKB PA448375 Link_out
Drug Product Database 587729 Link_out
RxList http://www.rxlist.com/cgi/generic3/cytadren.htm Link_out
Drugs.com http://www.drugs.com/cdi/aminoglutethimide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Aminoglutethimide Link_out
ATC Codes
  • L02BG01
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (122 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
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.
Food Interactions
  • Take without regard to meals.
Targets

1. Cytochrome P450 19A1

Pharmacological action: yes
Actions: inhibitor

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

Organism class: human
UniProt ID: P11511 Link_out
Gene: CYP19A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone

Organism class: human
UniProt ID: P05108 Link_out
Gene: CYP11A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inducer

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inducer

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inducer

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 imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19