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
Synonyms
  • Metirapona
  • Metopiron
  • Metyrapone
  • Metyraponum
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
METOPiRONECapsule, gelatin coated250 mg/1OralLaboratoire HRA Pharma2014-08-14Not applicableUs
International/Other Brands
Metopiron / Metopirone
Categories
UNII
ZS9KD92H6V
CAS number
54-36-4
Weight
Average: 226.2738
Monoisotopic: 226.11061308
Chemical Formula
C14H14N2O
InChI Key
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

Pharmacology

Indication

Used as a diagnostic drug for testing hypothalamic-pituitary ACTH function. Occasionally used in Cushing's syndrome.

Structured Indications
Not Available
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.

TargetActionsOrganism
ACytochrome P450 11B1, mitochondrial
inhibitor
Human
UCamphor 5-monooxygenase
other/unknown
Pseudomonas putida
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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Metyrapone.Approved
AripiprazoleThe serum concentration of Aripiprazole can be decreased when it is combined with Metyrapone.Approved, Investigational
ArtesunateThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Metyrapone resulting in a loss in efficacy.Approved
AtorvastatinThe risk or severity of adverse effects can be increased when Metyrapone is combined with Atorvastatin.Approved
BromocriptineThe risk or severity of adverse effects can be increased when Bromocriptine is combined with Metyrapone.Approved, Investigational
CabergolineThe risk or severity of adverse effects can be increased when Cabergoline is combined with Metyrapone.Approved
CerivastatinThe serum concentration of Cerivastatin can be increased when it is combined with Metyrapone.Withdrawn
DihydroergocornineThe risk or severity of adverse effects can be increased when Dihydroergocornine is combined with Metyrapone.Approved
DihydroergocristineThe risk or severity of adverse effects can be increased when Dihydroergocristine is combined with Metyrapone.Experimental
DihydroergocryptineThe risk or severity of adverse effects can be increased when Dihydroergocryptine is combined with Metyrapone.Experimental
DihydroergotamineThe risk or severity of adverse effects can be increased when Dihydroergotamine is combined with Metyrapone.Approved
ErgonovineThe risk or severity of adverse effects can be increased when Ergonovine is combined with Metyrapone.Approved
ErgotamineThe risk or severity of adverse effects can be increased when Ergotamine is combined with Metyrapone.Approved
FluvastatinThe serum concentration of Fluvastatin can be increased when it is combined with Metyrapone.Approved
FosphenytoinThe serum concentration of Metyrapone can be decreased when it is combined with Fosphenytoin.Approved
LisurideThe risk or severity of adverse effects can be increased when Lisuride is combined with Metyrapone.Approved
LovastatinThe serum concentration of Lovastatin can be increased when it is combined with Metyrapone.Approved, Investigational
Lysergic Acid DiethylamideThe risk or severity of adverse effects can be increased when Lysergic Acid Diethylamide is combined with Metyrapone.Illicit, Withdrawn
MetergolineThe risk or severity of adverse effects can be increased when Metergoline is combined with Metyrapone.Experimental
MethylergometrineThe risk or severity of adverse effects can be increased when Methylergometrine is combined with Metyrapone.Approved
MethysergideThe risk or severity of adverse effects can be increased when Methysergide is combined with Metyrapone.Approved
MevastatinThe serum concentration of Mevastatin can be increased when it is combined with Metyrapone.Experimental
NicergolineThe risk or severity of adverse effects can be increased when Nicergoline is combined with Metyrapone.Approved
PergolideThe risk or severity of adverse effects can be increased when Pergolide is combined with Metyrapone.Approved, Vet Approved, Withdrawn
PhenytoinThe serum concentration of Metyrapone can be decreased when it is combined with Phenytoin.Approved, Vet Approved
PitavastatinThe serum concentration of Pitavastatin can be increased when it is combined with Metyrapone.Approved
PravastatinThe serum concentration of Pravastatin can be increased when it is combined with Metyrapone.Approved
PropacetamolThe serum concentration of the active metabolites of Propacetamol can be increased when Propacetamol is used in combination with Metyrapone.Approved
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Metyrapone.Approved
SaxagliptinThe serum concentration of Saxagliptin can be decreased when it is combined with Metyrapone.Approved
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Metyrapone.Approved
TergurideThe risk or severity of adverse effects can be increased when Terguride is combined with Metyrapone.Experimental
UbidecarenoneThe serum concentration of Ubidecarenone can be increased when it is combined with Metyrapone.Experimental
Food Interactions
Not Available

References

Synthesis Reference
Not Available
General References
Not Available
External Links
Human Metabolome Database
HMDB15146
KEGG Drug
D00410
KEGG Compound
C07205
PubChem Compound
4174
PubChem Substance
46504862
ChemSpider
4030
BindingDB
50028166
ChEBI
44241
ChEMBL
CHEMBL934
Therapeutic Targets Database
DAP000424
PharmGKB
PA450486
HET
MYT
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Metyrapone
ATC Codes
V04CD01 — Metyrapone
AHFS Codes
Not Available
PDB Entries
1phg / 1w0g / 4zf8
FDA label
Not Available
MSDS
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedDiagnosticDepressive Disorder and Anxiety Disorders / Healthy Volunteers1
1CompletedTreatmentCocaine Use Disorders1
1CompletedTreatmentCocaine Use Disorders / Tobacco Use Disorders1
1Unknown StatusTreatmentCocaine-Related Disorders / Intravenous Infusions1
2CompletedTreatmentMajor Depressive Disorder (MDD)1
3CompletedTreatmentDepressive State1
3RecruitingTreatmentCushing's Syndrome1
4RecruitingBasic ScienceStress1
4Unknown StatusTreatmentBMI >30 kg/m2 / Insulin Resistance / Metabolic Syndromes1
Not AvailableCompletedTreatmentDependence, Cocaine1
Not AvailableUnknown StatusScreeningBrain Injury / Craniocerebral Trauma1

Pharmacoeconomics

Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Capsule, gelatin coatedOral250 mg/1
Prices
Unit descriptionCostUnit
Metopirone 250 mg capsule3.39USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)50.5 °CPhysProp
water solubilitySparingly solubleNot Available
logP1.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.427 mg/mLALOGPS
logP2.09ALOGPS
logP2.03ChemAxon
logS-2.7ALOGPS
pKa (Strongest Basic)4.87ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area42.85 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity65.94 m3·mol-1ChemAxon
Polarizability23.98 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9872
Blood Brain Barrier+0.985
Caco-2 permeable+0.7108
P-glycoprotein substrateNon-substrate0.6099
P-glycoprotein inhibitor INon-inhibitor0.6787
P-glycoprotein inhibitor IINon-inhibitor0.9579
Renal organic cation transporterNon-inhibitor0.8039
CYP450 2C9 substrateNon-substrate0.8174
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6282
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9484
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5382
Ames testNon AMES toxic0.907
CarcinogenicityNon-carcinogens0.8616
BiodegradationNot ready biodegradable0.9518
Rat acute toxicity2.6066 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9786
hERG inhibition (predictor II)Non-inhibitor0.8202
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-MSsplash10-05di-8930000000-51278af0b7707c808df8
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-QQ , positiveLC-MS/MSsplash10-004i-0090000000-c89f837f188fa67fb821
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-004i-0390000000-26267f0728adaecc8890
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00di-0900000000-419dc733a49ddd749433
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-05fr-0900000000-7aca9c1d7ea794878775
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-05fr-1900000000-4becb55b9b4a151284ab
LC-MS/MS Spectrum - LC-ESI-IT , positiveLC-MS/MSsplash10-00di-0900000000-ebc70b90c01f86b98551
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-1590000000-071c800b3f7a6a8740dc
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-3900100000-8f8a87e8debee126c12c

Taxonomy

Description
This compound belongs to the class of organic compounds known as aryl alkyl ketones. These are ketones have the generic structure RC(=O)R', where R = aryl group and R'=alkyl group.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbonyl compounds
Direct Parent
Aryl alkyl ketones
Alternative Parents
Pyridines and derivatives / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Aryl alkyl ketone / Pyridine / Heteroaromatic compound / Azacycle / Organoheterocyclic compound / Organic nitrogen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative / Organonitrogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
aromatic ketone (CHEBI:44241) / a small molecule (CPD-7023)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Steroid 11-beta-monooxygenase activity
Specific Function
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 cytochro...
Gene Name
CYP11B1
Uniprot ID
P15538
Uniprot Name
Cytochrome P450 11B1, mitochondrial
Molecular Weight
57572.44 Da
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:17462829]
  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:11869873]
  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:17487473]
  4. 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
Pseudomonas putida
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Iron ion binding
Specific Function
Involved in a camphor oxidation system.
Gene Name
camC
Uniprot ID
P00183
Uniprot Name
Camphor 5-monooxygenase
Molecular Weight
46668.8 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. 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:14741708]
  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:7619804]
  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:12237224]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 11-beta-monooxygenase activity
Specific Function
Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.
Gene Name
CYP11B2
Uniprot ID
P19099
Uniprot Name
Cytochrome P450 11B2, mitochondrial
Molecular Weight
57559.62 Da
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:17646925]
  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:9231789]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Details
3. Cytochrome P450 3A4
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 11-beta-monooxygenase activity
Specific Function
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 cytochro...
Gene Name
CYP11B1
Uniprot ID
P15538
Uniprot Name
Cytochrome P450 11B1, mitochondrial
Molecular Weight
57572.44 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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 ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Organic anion transmembrane transporter activity
Specific Function
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocyte...
Gene Name
ABCC3
Uniprot ID
O15438
Uniprot Name
Canalicular multispecific organic anion transporter 2
Molecular Weight
169341.14 Da
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:14570758]

Drug created on June 13, 2005 07:24 / Updated on October 02, 2017 04:50