METYRAPONE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H14N2O
Molecular Weight	226.2738
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)(C(=O)C1=CC=CN=C1)C2=CC=CN=C2

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

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf | https://www.drugs.com/cdi/metyrapone.html

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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cytochrome P450 11B1 9 Target ID: CHEMBL1908 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf \| https://www.drugbank.ca/drugs/DB01011 \| https://www.ncbi.nlm.nih.gov/pubmed/21129965	Inhibitor 8504		14.6 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Secondary adrenocortical insufficiency 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf http://adisinsight.springer.com/drugs/800035568	Diagnostic		Approved 8583	METOPIRONE Approved Use Metopirone is a diagnostic drug for testing hypothalamic‑pituitary ACTH function. Launch Date 1961

C_max

Value	Dose	Co-administered	Analyte	Population
3.7 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf	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
7.3 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.9 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012911s026lbl.pdf	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

Doses

Dose	Population	Adverse 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf	unknown, 6 years Health Status: unknown Age Group: 6 years Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (acute) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf
1600 mg 1 times / day steady, oral Dose: 1600 mg, 1 times / day Route: oral Route: steady Dose: 1600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26353009	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/26353009	Disc. AE: Gastrointestinal upset, Dizziness... AEs leading to discontinuation/dose reduction: Gastrointestinal upset (23%) Dizziness (23%) Sources: https://pubmed.ncbi.nlm.nih.gov/26353009

AEs

AE	Significance	Dose	Population
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf	unknown, 6 years Health Status: unknown Age Group: 6 years Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf
Dizziness	23% Disc. AE	1600 mg 1 times / day steady, oral Dose: 1600 mg, 1 times / day Route: oral Route: steady Dose: 1600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26353009	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/26353009
Gastrointestinal upset	23% Disc. AE	1600 mg 1 times / day steady, oral Dose: 1600 mg, 1 times / day Route: oral Route: steady Dose: 1600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26353009	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/26353009

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 inhibitor 2252 substrate 1946		inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP11B1 10 OATP1B1 1079 OATP1B3 961

Drug as perpetrator

Target	Modality	Activity
OATP1B1 1095	inhibitor 4027 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376123/pdf/nihms47229.pdf Page: 11.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376123/pdf/nihms47229.pdf Page: 11.0	no
CYP11B1 10	inhibitor 4027 Sources: https://link.springer.com/article/10.1016/S1734-1140(10)70363-7 Page: 5.0	yes
CYP2D6 2546	inhibitor 4027 Sources: https://link.springer.com/article/10.1016/S1734-1140(10)70363-7 Page: 5.0	yes
CYP3A4 2633	inducer 1966 Sources: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2265.2011.04214.x Page: 4.0	yes
CYP3A4 2633	inhibitor 4027 Sources: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2265.2011.04214.x Page: 4.0	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://www.mdpi.com/2218-273X/10/1/112 Page: 7.0	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:44241	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:44241
ChemicalBook	CB8329426	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8329426
eMolecules	531552	https://www.emolecules.com/cgi-bin/more?vid=531552
MolPort	MolPort-001-794-644	https://www.molport.com/shop/molecule-link/MolPort-001-794-644
ZINC	ZINC000000001728	http://zinc15.docking.org/substances/ZINC000000001728

PubMed

Title	Date	PubMed
Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.	2001 Aug 15	11522257
Primary culture system of adrenocortical cells from dogs to evaluate direct effects of chemicals on steroidogenesis.	2001 Aug 28	11522375
Rational, effective metyrapone treatment of ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH).	2001 Dec	11873864
Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression.	2001 Dec	11713467
Metabolism of territrem a by liver microsomes of Wistar rats: identification of the metabolites and their metabolic sequence.	2001 Dec 7	11760155
Involvement of adrenal and thyroid activity in the annual testicular regression of red headed bunting (Emberiza bruniceps).	2001 Jul	12017256
Involvement of the cholinergic pathway in the pathogenesis of pituitary Cushing's syndrome.	2001 Jun	11523900
Modulation of cyclophosphamide-based cytochrome P450 gene therapy using liver P450 inhibitors.	2001 Jun	11498765
Oxyphil metaplasia of adrenal cortex secondary to metyrapone therapy.	2001 Nov	11737320
Corticotropin secretory dynamics in humans under low glucocorticoid feedback.	2001 Nov	11701735
The role of adrenal corticosteroids in induction of micronuclei by morphine.	2001 Nov 15	11673078
Conservation of signaling pathways of xenobiotic-sensing orphan nuclear receptors, chicken xenobiotic receptor, constitutive androstane receptor, and pregnane X receptor, from birds to humans.	2001 Sep	11518807
Evidence that RDX biodegradation by Rhodococcus strain DN22 is plasmid-borne and involves a cytochrome p-450.	2002	12174045
The modulatory effects of corticosteroids on cognition: studies in young human populations.	2002 Apr	11818174
Evidence for involvement of glucocorticoid response in the hippocampal changes in aged molarless SAMP8 mice.	2002 Apr 1	11844579
Evidence for glucose-6-phosphate transport in rat liver microsomes.	2002 Apr 24	12062448
Metyrapone-induced corticosterone deficiency impairs glucose oxidation and steroidogenesis in Leydig cells of adult albino rats.	2002 Aug	12402971
Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones, plasma glucose and brain c-fos induction.	2002 Aug	12270045
Bench-to-bedside review: a possible resolution of the glucose paradox of cerebral ischemia.	2002 Aug	12225609
Target cells for cytochrome p450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands.	2002 Aug	12185414
Acute modulation of aged human memory by pharmacological manipulation of glucocorticoids.	2002 Aug	12161513
Deoxysarpagine hydroxylase--a novel enzyme closing a short side pathway of alkaloid biosynthesis in Rauvolfia.	2002 Aug	12057637
Glucocorticoid receptor deficient thymic and peripheral T cells develop normally in adult mice.	2002 Dec	12442337
Glucocorticoid involvement in memory formation in a rat model for traumatic memory.	2002 Feb	12171770
Reductive metabolism of p,p'-DDT and o,p'-DDT by rat liver cytochrome P450.	2002 Feb	11792678
A pharmacophore for human pregnane X receptor ligands.	2002 Jan	11744617
Biosynthesis of beta-substituted furan skeleton in the lower furanoterpenoids: a model study.	2002 Jan 11	11779213
Ectopic ACTH-syndrome due to a thymic carcinoid tumor.	2002 Jan-Feb	12017752
The role of cortisol suppression on craving for and satisfaction from nicotine in high and low impulsive subjects.	2002 Jul	12404678
Brain HSP70 mRNA expression is linked with plasma cortisol levels in goldfish (Carassius auratus) exposed to a potential predator.	2002 Jul	12149573
Metyrapone for Cushing's syndrome.	2002 Jul	12091216
Functional scintigraphy of the adrenal gland.	2002 Jul	12088915
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	12369251
Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management.	2002 Jun	12050244
The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities.	2002 Jun	12021197
Small changes in whole-body corticosterone content affect larval Rana pipiens fitness components.	2002 Jun 1	12161197
Induction of cardiac cytochrome p450 in cocaine-treated mice.	2002 Mar	11856816
Residual symptoms in depression an emerging therapeutic concept.	2002 May	12188108
Leukemia inhibitory factor is a mediator of Escherichia coli lipopolysaccharide-induced acute thymic atrophy.	2002 Nov	12385026
Cushing's syndrome during pregnancy: curative adrenalectomy at 31 weeks gestation.	2002 Nov 15	12381486
The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.	2002 Oct	12372848
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	12364444
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	12297537
Does cortisol mediate endotoxin-induced inhibition of pulsatile luteinizing hormone and gonadotropin-releasing hormone secretion?	2002 Oct	12239084
Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral-chiral chromatography.	2002 Oct	12237834
The contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazine neuroleptics.	2002 Oct	12208554
Responses of the bronchial and pulmonary circulations to short-term nitric oxide inhalation before and after endotoxaemia in the pig.	2002 Sep	12193221
Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function.	2002 Sep 1	12182973
Spectroscopic studies of peroxyacetic acid reaction intermediates of cytochrome P450cam and chloroperoxidase.	2002 Sep 20	12237224
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	12456705

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

Metyrapone (IC50) of 1 uM) inhibited the apparent CYP11B1 activity in the H295R human adrenocortical carcinoma cell line.

Name

Type

Language

METOPIRONE

Preferred Name

English

METYRAPONE

Official 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 [WHO-DD]

Common Name

English

METYRAPONE [VANDF]

Common Name

English

metyrapone [INN]

Common Name

English

METYRAPONE [ORANGE BOOK]

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