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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
SynonymsNot 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 KeyInChIKey=FJLBFSROUSIWMA-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
    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

    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

    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

    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
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13