You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameMetyrapone
Accession NumberDB01011  (APRD01111, EXPT02271)
Typesmall molecule
Groupsapproved
Description

An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of cushing syndrome. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
MetiraponaNot AvailableNot Available
MetopironNot AvailableNot Available
MetopironeNot AvailableNot Available
MetyraponeNot AvailableNot Available
MetyraponumNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
MetopironNot Available
MetopironeNot Available
Brand mixturesNot Available
Categories
CAS number54-36-4
WeightAverage: 226.2738
Monoisotopic: 226.11061308
Chemical FormulaC14H14N2O
InChI KeyFJLBFSROUSIWMA-UHFFFAOYSA-N
InChI
InChI=1S/C14H14N2O/c1-14(2,12-6-4-8-16-10-12)13(17)11-5-3-7-15-9-11/h3-10H,1-2H3
IUPAC Name
2-methyl-1,2-bis(pyridin-3-yl)propan-1-one
SMILES
CC(C)(C(=O)C1=CN=CC=C1)C1=CN=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPyridines and Derivatives
SubclassNot Available
Direct parentPyridines and Derivatives
Alternative parentsKetones; Polyamines; Enolates
Substituentsketone; enolate; polyamine; organonitrogen compound; carbonyl group
Classification descriptionThis compound belongs to the pyridines and derivatives. These are compounds containing a pyridine ring, which is a six-member aromatic heterocycle which consists of one nitrogen atom and five carbon atoms.
Pharmacology
IndicationUsed as a diagnostic drug for testing hypothalamic-pituitary ACTH function. Occasionally used in Cushing's syndrome.
PharmacodynamicsMetopirone is an inhibitor of endogenous adrenal corticosteroid synthesis.
Mechanism of actionThe pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-ß-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.
AbsorptionAbsorbed rapidly and well when administered orally. Peak plasma concentrations are usually reached 1 hour after administration.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic. The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Metyrapone and metyrapol are both conjugated with glucuronide.

SubstrateEnzymesProduct
Metyrapone
Not Available
MetyrapolDetails
Route of eliminationAfter administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.
Half life1.9 ±0.7 hours.
ClearanceNot Available
ToxicityOral LD50 in rats is 521 mg/kg. One case has been recorded in which a 6-year-old girl died after two doses of Metopirone, 2 g. Symptoms of overdose include cardiac arrhythmias, hypotension, dehydration, anxiety, confusion, weakness, impairment of consciousness, nausea, vomiting, epigastric pain, and diarrhea.
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 + 0.9872
Blood Brain Barrier + 0.985
Caco-2 permeable + 0.7108
P-glycoprotein substrate Non-substrate 0.6099
P-glycoprotein inhibitor I Non-inhibitor 0.6787
P-glycoprotein inhibitor II Non-inhibitor 0.9579
Renal organic cation transporter Non-inhibitor 0.8039
CYP450 2C9 substrate Non-substrate 0.8174
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.6282
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9484
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Inhibitor 0.7959
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5382
Ames test Non AMES toxic 0.907
Carcinogenicity Non-carcinogens 0.8616
Biodegradation Not ready biodegradable 0.9518
Rat acute toxicity 2.6066 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9786
hERG inhibition (predictor II) Non-inhibitor 0.8202
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Metopirone 250 mg capsule3.39USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point50.5 °CPhysProp
water solubilitySparingly solubleNot Available
logP1.8Not Available
Predicted Properties
PropertyValueSource
water solubility4.27e-01 g/lALOGPS
logP2.09ALOGPS
logP2.03ChemAxon
logS-2.7ALOGPS
pKa (strongest basic)4.87ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count0ChemAxon
polar surface area42.85ChemAxon
rotatable bond count3ChemAxon
refractivity65.94ChemAxon
polarizability23.98ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00410
KEGG CompoundC07205
PubChem Compound4174
PubChem Substance46504862
ChemSpider4030
ChEBI6911
ChEMBLCHEMBL934
Therapeutic Targets DatabaseDAP000424
PharmGKBPA450486
HETMYT
RxListhttp://www.rxlist.com/cgi/generic3/metopirone.htm
Drugs.comhttp://www.drugs.com/cdi/metyrapone.html
WikipediaMetyrapone
ATC CodesV04CD01
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
CyproheptadineThis combination renders test invalid
FosphenytoinThe combination renders the test invalid
PhenytoinThe combination renders the test invalid
Food InteractionsNot Available

Targets

1. Cytochrome P450 11B1, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 11B1, mitochondrial P15538 Details

References:

  1. Young EA, Ribeiro SC, Ye W: Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression. Psychoneuroendocrinology. 2007 Jun;32(5):503-7. Epub 2007 Apr 25. Pubmed
  2. Johansson MK, Sanderson JT, Lund BO: Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line. Toxicol In Vitro. 2002 Apr;16(2):113-21. Pubmed
  3. Hermansson V, Asp V, Bergman A, Bergstrom U, Brandt I: Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p’-DDD in Y-1 adrenal cells. Arch Toxicol. 2007 Nov;81(11):793-801. Epub 2007 May 9. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Camphor 5-monooxygenase

Kind: protein

Organism: Pseudomonas putida

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Camphor 5-monooxygenase P00183 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. Bistolas N, Christenson A, Ruzgas T, Jung C, Scheller FW, Wollenberger U: Spectroelectrochemistry of cytochrome P450cam. Biochem Biophys Res Commun. 2004 Feb 13;314(3):810-6. Pubmed
  4. Shiro Y, Fujii M, Isogai Y, Adachi S, Iizuka T, Obayashi E, Makino R, Nakahara K, Shoun H: Iron-ligand structure and iron redox property of nitric oxide reductase cytochrome P450nor from Fusarium oxysporum: relevance to its NO reduction activity. Biochemistry. 1995 Jul 18;34(28):9052-8. Pubmed
  5. Schunemann V, Jung C, Terner J, Trautwein AX, Weiss R: Spectroscopic studies of peroxyacetic acid reaction intermediates of cytochrome P450cam and chloroperoxidase. J Inorg Biochem. 2002 Sep 20;91(4):586-96. Pubmed

Enzymes

1. Cytochrome P450 11B2, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 11B2, mitochondrial P19099 Details

References:

  1. Roumen L, Sanders MP, Pieterse K, Hilbers PA, Plate R, Custers E, de Gooyer M, Smits JF, Beugels I, Emmen J, Ottenheijm HC, Leysen D, Hermans JJ: Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics. J Comput Aided Mol Des. 2007 Aug;21(8):455-71. Epub 2007 Jul 24. Pubmed
  2. Gomez-Sanchez CE, Zhou MY, Cozza EN, Morita H, Foecking MF, Gomez-Sanchez EP: Aldosterone biosynthesis in the rat brain. Endocrinology. 1997 Aug;138(8):3369-73. Pubmed

2. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 11B1, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 11B1, mitochondrial P15538 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Transporters

1. Canalicular multispecific organic anion transporter 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 2 O15438 Details

References:

  1. Teng S, Jekerle V, Piquette-Miller M: Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab Dispos. 2003 Nov;31(11):1296-9. Pubmed

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13