METYRAPONE TARTRATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C14H14N2O.2C4H6O6
Molecular Weight	526.4474
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O[C@H]([C@@H](O)C(O)=O)C(O)=O.O[C@H]([C@@H](O)C(O)=O)C(O)=O.CC(C)(C(=O)C1=CN=CC=C1)C2=CC=CN=C2

InChI

InChIKey=FBSAWAHQGRDEJD-WBPXWQEISA-N

InChI=1S/C14H14N2O.2C4H6O6/c1-14(2,12-6-4-8-16-10-12)13(17)11-5-3-7-15-9-11;2*5-1(3(7)8)2(6)4(9)10/h3-10H,1-2H3;2*1-2,5-6H,(H,7,8)(H,9,10)/t;2*1-,2-/m.11/s1

HIDE SMILES / InChI

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

Molecular Formula	C4H6O6
Molecular Weight	150.0868
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

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 8228		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 8360	METOPIRONE Approved Use Metopirone is a diagnostic drug for testing hypothalamic‑pituitary ACTH function. Launch Date -2.54880006E11

C_max

Value	Dose	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
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 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

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

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
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf	unknown, 6 years n = 1 Health Status: unknown Age Group: 6 years Sex: F Population Size: 1 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 (mean) 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 n = 48 Health Status: unhealthy Condition: Cushing's Syndrome Population Size: 48 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 n = 1 Health Status: unknown Age Group: 6 years Sex: F Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012911s036lbl.pdf
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: https://pubmed.ncbi.nlm.nih.gov/26353009	unhealthy n = 48 Health Status: unhealthy Condition: Cushing's Syndrome Population Size: 48 Sources: https://pubmed.ncbi.nlm.nih.gov/26353009
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: https://pubmed.ncbi.nlm.nih.gov/26353009	unhealthy n = 48 Health Status: unhealthy Condition: Cushing's Syndrome Population Size: 48 Sources: https://pubmed.ncbi.nlm.nih.gov/26353009

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 768 inhibitor 1579 substrate 1709		inhibitor 1837

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP11B1 10 OATP1B1 781 OATP1B3 700

Drug as perpetrator

Target	Modality	Activity
OATP1B1 796	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376123/pdf/nihms47229.pdf Page: 11.0	no
OATP1B3 709	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376123/pdf/nihms47229.pdf Page: 11.0	no
CYP11B1 10	inhibitor 3240 Sources: https://link.springer.com/article/10.1016/S1734-1140(10)70363-7 Page: 5.0	yes
CYP2D6 1875	inhibitor 3240 Sources: https://link.springer.com/article/10.1016/S1734-1140(10)70363-7 Page: 5.0	yes
CYP3A4 1909	inducer 1542 Sources: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2265.2011.04214.x Page: 4.0	yes
CYP3A4 1909	inhibitor 3240 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 1709	substrate 3326 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
MolPort	MolPort-001-794-644	https://www.molport.com/shop/molecule-link/MolPort-001-794-644
ZINC	ZINC000000001728	http://zinc15.docking.org/substances/ZINC000000001728
eMolecules	531552	https://www.emolecules.com/cgi-bin/more?vid=531552

PubMed

Title	Date	PubMed
In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I.	2000 Feb	10664531
Isolation and characterization of two aerobic bacterial strains that completely degrade ethyl tert-butyl ether (ETBE).	2001 Apr	11341318
Appetite-suppressing effects of urotensin I and corticotropin-releasing hormone in goldfish (Carassius auratus).	2001 Apr	11340339
Cytochrome P450 1A1 and 4A activities in isolated rat spleen lymphocytes.	2001 Apr	11338675
Diagnosis of adrenal cortical dysfunction by liquid chromatography-tandem mass spectrometry.	2001 Apr	11337910
Bioactivation and cytotoxicity of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) in isolated rat hepatocytes.	2001 Apr	11322177
The role of glutathione reductase in the cytotoxicity of chromium (VI) in isolated rat hepatocytes.	2001 Apr 16	11311213
Induction by xenobiotics of phase I and phase II enzyme activities in the human keratinocyte cell line NCTC 2544.	2001 Dec	11698172
Preischemic hyperglycemia-aggravated damage: evidence that lactate utilization is beneficial and glucose-induced corticosterone release is detrimental.	2001 Dec 1	11746402
Adrenal insufficiency in HIV infection: a review and recommendations.	2001 Feb	11217816
Recurrent ACTH-independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone.	2001 Feb	11207645
Human glucocorticoid feedback inhibition is reduced in older individuals: evening study.	2001 Feb	11158007
Long term modulation of the HPA axis by the hippocampus. Behavioral, biochemical and immunological endpoints in rats exposed to chronic mild stress.	2001 Feb	11087960
Species- and tissue-specific physiological regulation of vasopressin mRNA poly(A) tail length.	2001 Feb 7	11161001
Pathogenesis of carbon tetrachloride-induced hepatocyte injury bioactivation of CCI4 by cytochrome P450 and effects on lipid homeostasis.	2001 Jan-Feb	11302200
Involvement of adrenal and thyroid activity in the annual testicular regression of red headed bunting (Emberiza bruniceps).	2001 Jul	12017256
Prodissociative effects of metyrapone.	2001 Jul	11431246
Lung carcinoid related Cushing's syndrome: report of three cases and review of the literature.	2001 Jul	11423600
Role of crotoxin, a phospholipase A2 isolated from Crotalus durissus terrificus snake venom, on inflammatory and immune reactions.	2001 Jun	11545249
Modulation of cyclophosphamide-based cytochrome P450 gene therapy using liver P450 inhibitors.	2001 Jun	11498765
Fatal liver failure due to ketoconazole treatment of a girl with Cushing's syndrome.	2001 Mar	11308052
The role of adrenal corticosteroids in induction of micronuclei by morphine.	2001 Nov 15	11673078
No effect of the cortisol-synthesis inhibitor metyrapone on alcohol drinking: a pilot study.	2001 Oct	11747981
Protective effects of 5-HT1A receptor agonists against emotional changes produced by stress stimuli are related to their neuroendocrine effects.	2001 Oct	11588113
The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency.	2002 Apr	11966747
Evidence for involvement of glucocorticoid response in the hippocampal changes in aged molarless SAMP8 mice.	2002 Apr 1	11844579
Production of carbon monoxide by cytochrome P450 during iron-dependent lipid peroxidation.	2002 Feb	11812634
A lipid A analog ONO-4007 induces tolerance to plasma leakage in mice.	2002 Jan	11845997
A pharmacophore for human pregnane X receptor ligands.	2002 Jan	11744617
Role for corticoids in mediating the response of Rana pipiens tadpoles to intraspecific competition.	2002 Jan 1	11754020
Metyrapone for Cushing's syndrome.	2002 Jul	12091216
Functional scintigraphy of the adrenal gland.	2002 Jul	12088915
The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities.	2002 Jun	12021197
Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis.	2002 Mar	11889204
Does cortisol mediate endotoxin-induced inhibition of pulsatile luteinizing hormone and gonadotropin-releasing hormone secretion?	2002 Oct	12239084
The contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazine neuroleptics.	2002 Oct	12208554
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.

Substance Class	Chemical Created by `admin` on `Wed Jul 05 22:42:08 UTC 2023` Edited by `admin` on `Wed Jul 05 22:42:08 UTC 2023`
Record UNII	B6DRB5ZI7P
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

METYRAPONE TARTRATE

Official Name

English

Metyrapone tartrate [WHO-DD]

Common Name

English

METOPIRONE DITARTRATE

Brand Name

English

METYRAPONE TARTRATE [USAN]

Common Name

English

1-PROPANONE, 2-METHYL-1,2-DI-3-PYRIDINYL-, (R-(R*,R*))-2,3-DIHYDROXYBUTANEDIOATE (1:2)

Common Name

English

SU-4885

Code

English

2-Methyl-1,2-di-3-pyridyl-1-propanone tartrate (1:2)

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C471