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Identification
Name Metyrapone
Accession Number DB01011 (APRD01111, EXPT02271)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Mepyrapone
Methapyrapone
Methbipyranone
Methopirapone
Methopyrapone
Methopyrinine
Methopyrone
Metroprione
Metyrapon
Salts Not Available
Brand names
Name Company
Metapirone
Metapyron
Metopiron
Metopirone
Metopyrone
Brand mixtures Not Available
Categories
  • Antimetabolites
  • Enzyme Inhibitors
CAS number 54-36-4
Weight Average: 226.2738
Monoisotopic: 226.11061308
Chemical Formula C14H14N2O
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbonyl Compounds
  • Pyridines and Derivatives
Substructures
  • Carbonyl Compounds
  • Pyridines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Ketones
Pharmacology
Indication Used as a diagnostic drug for testing hypothalamic-pituitary ACTH function. Occasionally used in Cushing's syndrome.
Pharmacodynamics Metopirone is an inhibitor of endogenous adrenal corticosteroid synthesis.
Mechanism of action The 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.
Absorption Absorbed rapidly and well when administered orally. Peak plasma concentrations are usually reached 1 hour after administration.
Volume of distribution Not Available
Protein binding Not 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.
Route of elimination After 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 life 1.9 ±0.7 hours.
Clearance Not Available
Toxicity Oral 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Metopirone 250 mg capsule 3.39 USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 50.5 °C PhysProp
water solubility Sparingly soluble Not Available
logP 1.8 Not Available
Predicted Properties
Property Value Source
water solubility 4.27e-01 g/l ALOGPS
logP 2.09 ALOGPS
logP 2.03 ChemAxon
logS -2.7 ALOGPS
pKa (strongest basic) 4.87 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 42.85 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 65.94 ChemAxon
polarizability 23.98 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00410 Link_out
KEGG Compound C07205 Link_out
PubChem Compound 4174 Link_out
PubChem Substance 46504862 Link_out
ChemSpider 4030 Link_out
ChEBI 6911 Link_out
ChEMBL 6911 Link_out
Therapeutic Targets Database DAP000424 Link_out
PharmGKB PA450486 Link_out
HET MYT Link_out
RxList http://www.rxlist.com/cgi/generic3/metopirone.htm Link_out
Drugs.com http://www.drugs.com/cdi/metyrapone.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Metyrapone Link_out
ATC Codes
  • V04CD01
AHFS Codes Not Available
PDB Entries
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Cyproheptadine This combination renders test invalid
Fosphenytoin The combination renders the test invalid
Phenytoin The combination renders the test invalid
Food Interactions Not Available
Targets

1. Cytochrome P450 11B1, mitochondrial

Pharmacological action: yes
Actions: inhibitor

Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB

Organism class: human
UniProt ID: P15538 Link_out
Gene: CYP11B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Cytochrome P450-cam

Pharmacological action: unknown
Actions: other/unknown

Involved in a camphor oxidation system

Organism class: bacterial
UniProt ID: P00183 Link_out
Gene: camC
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. 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

Actions: inhibitor

Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone

UniProt ID: P19099 Link_out
Gene: CYP11B2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase

UniProt ID: P11509 Link_out
Gene: CYP2A6
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor, 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. 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

Actions: inhibitor

Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB

UniProt ID: P15538 Link_out
Gene: CYP11B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inducer

May act as an inducible transporter in the biliary and intestinal excretion of organic anions

UniProt ID: O15438 Link_out
Gene: ABCC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19