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
SMILES
CC(C)(C(=O)C1=CN=CC=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
Molecular Formula | C14H14N2O |
Molecular Weight | 226.2738 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
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
Sources: http://adisinsight.springer.com/drugs/800035568
Curator's Comment: # Novartis
Approval Year
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27265478 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
219.6 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27265478 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27265478 |
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
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: |
unknown, 6 years n = 1 Health Status: unknown Age Group: 6 years Sex: F Population Size: 1 Sources: |
Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (acute) Sources: |
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%) Sources: Dizziness (23%) |
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: |
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
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 11.0 |
no | |||
Page: 11.0 |
no | |||
Page: 5.0 |
yes | |||
Page: 5.0 |
yes | |||
Page: 4.0 |
yes | |||
Page: 4.0 |
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.mdpi.com/2218-273X/10/1/112 Page: 7.0 |
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Biology of posttraumatic stress disorder. | 2001 |
|
Isolation and characterization of two aerobic bacterial strains that completely degrade ethyl tert-butyl ether (ETBE). | 2001 Apr |
|
Glucocorticoid and mineralocorticoid receptors are involved in the facilitation of anxiety-like response induced by restraint. | 2001 Apr |
|
Diagnosis of adrenal cortical dysfunction by liquid chromatography-tandem mass spectrometry. | 2001 Apr |
|
Metabolism of territrem a by liver microsomes of Wistar rats: identification of the metabolites and their metabolic sequence. | 2001 Dec 7 |
|
Bioactivation to free radicals and cytotoxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b). | 2001 Feb |
|
A novel drug-regulated gene expression system based on the nuclear receptor constitutive androstane receptor (CAR). | 2001 Feb |
|
Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture. | 2001 Feb |
|
Pathogenesis of carbon tetrachloride-induced hepatocyte injury bioactivation of CCI4 by cytochrome P450 and effects on lipid homeostasis. | 2001 Jan-Feb |
|
Prodissociative effects of metyrapone. | 2001 Jul |
|
Role of crotoxin, a phospholipase A2 isolated from Crotalus durissus terrificus snake venom, on inflammatory and immune reactions. | 2001 Jun |
|
Altered HPA axis responsivity to metyrapone testing in methadone maintained former heroin addicts with ongoing cocaine addiction. | 2001 May |
|
Corticotropin secretory dynamics in humans under low glucocorticoid feedback. | 2001 Nov |
|
The role of adrenal corticosteroids in induction of micronuclei by morphine. | 2001 Nov 15 |
|
No effect of the cortisol-synthesis inhibitor metyrapone on alcohol drinking: a pilot study. | 2001 Oct |
|
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 |
|
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 |
|
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 |
|
The role of cortisol suppression on craving for and satisfaction from nicotine in high and low impulsive subjects. | 2002 Jul |
|
Metyrapone for Cushing's syndrome. | 2002 Jul |
|
Functional scintigraphy of the adrenal gland. | 2002 Jul |
|
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 |
|
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 |
|
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
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11869873
Metyrapone (IC50) of 1 uM) inhibited the apparent CYP11B1 activity in the H295R human adrenocortical carcinoma cell line.
Substance Class |
Chemical
Created
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Record UNII |
ZS9KD92H6V
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NDF-RT |
N0000175921
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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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DB01011
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METYRAPONE
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Metyrapone
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ACTIVE MOIETY |