U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C14H14N2O
Molecular Weight 226.2743
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of METYRAPONE

SMILES

CC(C)(c1cccnc1)C(=O)c2cccnc2

InChI

InChIKey=FJLBFSROUSIWMA-UHFFFAOYSA-N
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

HIDE SMILES / InChI
Metyrapone (trade name Metopirone) is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). Metopirone, metyrapone USP, is an inhibitor of endogenous adrenal corticosteroid synthesis, available as 250-mg capsules for oral administration. The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-β-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.

Originator

Curator's Comment:: # Novartis

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Diagnostic
METOPIRONE

Approved Use

Metopirone is a diagnostic drug for testing hypothalamic‑pituitary ACTH function.

Launch Date

-2.54880006E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
3.7 μg/mL
750 mg single, oral
dose: 750 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
METYRAPONE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
255.5 ng/mL
50 mg/kg single, oral
dose: 50 mg/kg
route of administration: Oral
experiment type: SINGLE
co-administered:
METYRAPONE plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
7.3 μg/mL
2000 mg single, oral
dose: 2000 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
METYRAPONE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
219.6 ng × h/mL
50 mg/kg single, oral
dose: 50 mg/kg
route of administration: Oral
experiment type: SINGLE
co-administered:
METYRAPONE plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
1.9 h
750 mg single, oral
dose: 750 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
METYRAPONE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
0.99 h
50 mg/kg single, oral
dose: 50 mg/kg
route of administration: Oral
experiment type: SINGLE
co-administered:
METYRAPONE plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
2 g 2 times / day steady, oral
Overdose
Dose: 2 g, 2 times / day
Route: oral
Route: steady
Dose: 2 g, 2 times / day
Sources:
unknown, 6 years
n = 1
Health Status: unknown
Age Group: 6 years
Sex: F
Population Size: 1
Sources:
Other AEs: Toxic reaction (NOS)...
1600 mg 1 times / day steady, oral (mean)
Dose: 1600 mg, 1 times / day
Route: oral
Route: steady
Dose: 1600 mg, 1 times / day
Sources:
unhealthy
n = 48
Health Status: unhealthy
Condition: Cushing's Syndrome
Population Size: 48
Sources:
Disc. AE: Gastrointestinal upset, Dizziness...
AEs leading to
discontinuation/dose reduction:
Gastrointestinal upset (23%)
Dizziness (23%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Toxic reaction (NOS) acute
2 g 2 times / day steady, oral
Overdose
Dose: 2 g, 2 times / day
Route: oral
Route: steady
Dose: 2 g, 2 times / day
Sources:
unknown, 6 years
n = 1
Health Status: unknown
Age Group: 6 years
Sex: F
Population Size: 1
Sources:
Dizziness 23%
Disc. AE
1600 mg 1 times / day steady, oral (mean)
Dose: 1600 mg, 1 times / day
Route: oral
Route: steady
Dose: 1600 mg, 1 times / day
Sources:
unhealthy
n = 48
Health Status: unhealthy
Condition: Cushing's Syndrome
Population Size: 48
Sources:
Gastrointestinal upset 23%
Disc. AE
1600 mg 1 times / day steady, oral (mean)
Dose: 1600 mg, 1 times / day
Route: oral
Route: steady
Dose: 1600 mg, 1 times / day
Sources:
unhealthy
n = 48
Health Status: unhealthy
Condition: Cushing's Syndrome
Population Size: 48
Sources:
Overview

Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer



Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
PubMed

PubMed

TitleDatePubMed
[Pituitary function after transsphenoidal surgery for pituitary adenoma].
2001
Rational, effective metyrapone treatment of ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH).
2001 Dec
Preischemic hyperglycemia-aggravated damage: evidence that lactate utilization is beneficial and glucose-induced corticosterone release is detrimental.
2001 Dec 1
Metabolism of territrem a by liver microsomes of Wistar rats: identification of the metabolites and their metabolic sequence.
2001 Dec 7
Oxyphil metaplasia of adrenal cortex secondary to metyrapone therapy.
2001 Nov
No effect of the cortisol-synthesis inhibitor metyrapone on alcohol drinking: a pilot study.
2001 Oct
Evidence that RDX biodegradation by Rhodococcus strain DN22 is plasmid-borne and involves a cytochrome p-450.
2002
Sympathetic nervous system plays a major role in acute cold/restraint stress inhibition of host resistance to Listeria monocytogenes.
2002 Apr
Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line.
2002 Apr
The modulatory effects of corticosteroids on cognition: studies in young human populations.
2002 Apr
Evidence for involvement of glucocorticoid response in the hippocampal changes in aged molarless SAMP8 mice.
2002 Apr 1
Evidence for glucose-6-phosphate transport in rat liver microsomes.
2002 Apr 24
Metyrapone-induced corticosterone deficiency impairs glucose oxidation and steroidogenesis in Leydig cells of adult albino rats.
2002 Aug
Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones, plasma glucose and brain c-fos induction.
2002 Aug
Bench-to-bedside review: a possible resolution of the glucose paradox of cerebral ischemia.
2002 Aug
Target cells for cytochrome p450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands.
2002 Aug
Acute modulation of aged human memory by pharmacological manipulation of glucocorticoids.
2002 Aug
Deoxysarpagine hydroxylase--a novel enzyme closing a short side pathway of alkaloid biosynthesis in Rauvolfia.
2002 Aug
Glucocorticoid receptor deficient thymic and peripheral T cells develop normally in adult mice.
2002 Dec
Glucocorticoid involvement in memory formation in a rat model for traumatic memory.
2002 Feb
Production of carbon monoxide by cytochrome P450 during iron-dependent lipid peroxidation.
2002 Feb
Reductive metabolism of p,p'-DDT and o,p'-DDT by rat liver cytochrome P450.
2002 Feb
A lipid A analog ONO-4007 induces tolerance to plasma leakage in mice.
2002 Jan
Circulating corticosterone alters the rate of neuropathological and behavioral changes induced by trimethyltin in rats.
2002 Jan
A pharmacophore for human pregnane X receptor ligands.
2002 Jan
Biosynthesis of beta-substituted furan skeleton in the lower furanoterpenoids: a model study.
2002 Jan 11
The role of cortisol suppression on craving for and satisfaction from nicotine in high and low impulsive subjects.
2002 Jul
Brain HSP70 mRNA expression is linked with plasma cortisol levels in goldfish (Carassius auratus) exposed to a potential predator.
2002 Jul
Metyrapone for Cushing's syndrome.
2002 Jul
Functional scintigraphy of the adrenal gland.
2002 Jul
Erratum to "CNS drugs in Cushing's disease: pathophysiological and therapeutic implications for mood disorders" [Prog. Neuro-Psycol. Biol. Psychiatry, 26, 763 (2002)].
2002 Jun
Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management.
2002 Jun
The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities.
2002 Jun
Small changes in whole-body corticosterone content affect larval Rana pipiens fitness components.
2002 Jun 1
Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis.
2002 Mar
Induction of cardiac cytochrome p450 in cocaine-treated mice.
2002 Mar
Residual symptoms in depression an emerging therapeutic concept.
2002 May
Transcriptional activation of cytochrome P450 CYP2C45 by drugs is mediated by the chicken xenobiotic receptor (CXR) interacting with a phenobarbital response enhancer unit.
2002 May 3
Leukemia inhibitory factor is a mediator of Escherichia coli lipopolysaccharide-induced acute thymic atrophy.
2002 Nov
Cushing's syndrome during pregnancy: curative adrenalectomy at 31 weeks gestation.
2002 Nov 15
The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.
2002 Oct
The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans.
2002 Oct
Leptin receptor expression in the rat placenta: changes in ob-ra, ob-rb, and ob-re with gestational age and suppression by glucocorticoids.
2002 Oct
Does cortisol mediate endotoxin-induced inhibition of pulsatile luteinizing hormone and gonadotropin-releasing hormone secretion?
2002 Oct
Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral-chiral chromatography.
2002 Oct
The contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazine neuroleptics.
2002 Oct
Responses of the bronchial and pulmonary circulations to short-term nitric oxide inhalation before and after endotoxaemia in the pig.
2002 Sep
Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function.
2002 Sep 1
Spectroscopic studies of peroxyacetic acid reaction intermediates of cytochrome P450cam and chloroperoxidase.
2002 Sep 20
Exposure of brown trout Salmo trutta to a sublethal concentration of copper in soft acidic water: effects upon gas exchange and ammonia accumulation.
2003 Jan
Patents

Patents

Sample Use Guides

Single-Dose Short Test This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone (Metyrapone). The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate. Multiple-Dose Test Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS. Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed. Day 3-4: Rest period. Day 5: Administration of Metopirone: Recommended with milk or snack. Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg. Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended. Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.
Route of Administration: Oral
Metyrapone (IC50) of 1 uM) inhibited the apparent CYP11B1 activity in the H295R human adrenocortical carcinoma cell line.
Name Type Language
METYRAPONE
HSDB   INN   MART.   MI   ORANGE BOOK   USAN   USP   USP-RS   VANDF   WHO-DD  
INN   USAN  
Official Name English
METOPIRONE
Brand Name English
METYRAPONE [MART.]
Common Name English
METYRAPONE [HSDB]
Common Name English
METYRAPONE [USP MONOGRAPH]
Common Name English
2-METHYL-1,2-DI-3-PYRIDYL-1-PROPANONE
Systematic Name English
METYRAPONE [VANDF]
Common Name English
METYRAPONE [INN]
Common Name English
METYRAPONE [ORANGE BOOK]
Common Name English
METYRAPONE [WHO-DD]
Common Name English
METYRAPONE [USP-RS]
Common Name English
1-PROPANONE, 2-METHYL-1,2-DI-3-PYRIDINYL-
Systematic Name English
NSC-25265
Code English
METYRAPONE [JAN]
Common Name English
METYRAPONE [USAN]
Common Name English
METYRAPONE [MI]
Common Name English
Classification Tree Code System Code
NDF-RT N0000175921
Created by admin on Fri Jun 25 20:53:46 UTC 2021 , Edited by admin on Fri Jun 25 20:53:46 UTC 2021
WHO-ATC V04CD01
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FDA ORPHAN DRUG 377212
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NDF-RT N0000175928
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NCI_THESAURUS C471
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WHO-VATC QV04CD01
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Code System Code Type Description
ECHA (EC/EINECS)
200-206-2
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PRIMARY
NCI_THESAURUS
C47619
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PRIMARY
PUBCHEM
4174
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PRIMARY
USP_CATALOG
1443001
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PRIMARY USP-RS
DRUG BANK
DB01011
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PRIMARY
WIKIPEDIA
METYRAPONE
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PRIMARY
FDA UNII
ZS9KD92H6V
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PRIMARY
ChEMBL
CHEMBL934
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PRIMARY
MESH
D008797
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PRIMARY
INN
1404
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PRIMARY
EVMPD
SUB08925MIG
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PRIMARY
IUPHAR
5224
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PRIMARY
HSDB
2500
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PRIMARY
DRUG CENTRAL
1791
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PRIMARY
CAS
54-36-4
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PRIMARY
EPA CompTox
54-36-4
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PRIMARY
MERCK INDEX
M7508
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PRIMARY Merck Index
RXCUI
6923
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PRIMARY RxNorm
LACTMED
Metyrapone
Created by admin on Fri Jun 25 20:53:46 UTC 2021 , Edited by admin on Fri Jun 25 20:53:46 UTC 2021
PRIMARY