-metyrapone

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/02 22:55:47」(JST)

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Metyrapone (trade name Metopirone) is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism).

Mechanism[edit]

Metyrapone blocks cortisol synthesis^[1] by inhibiting steroid 11β-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11-deoxycortisol levels.

Uses[edit]

Metyrapone can be used in the diagnosis of adrenal insufficiency. Metyrapone 30 mg/kg, maximum dose 3000 mg, is administered at midnight usually with a snack. The plasma cortisol and 11-deoxycortisol are measured the next morning between 8:00 and 9:00 am. A plasma cortisol less than 220 nmol/l indicates adequate inhibition of 11β-hydroxylase. In patients with intact Hypothalamo-pituitary-adrenal axis, CRH and ACTH levels rise as a response to the falling cortisol levels. This results in an increase of the steroid precursors in the pathway. Therefore if 11-deoxycortisol levels do not rise and remains less than 7 µg/dl and ACTH rises, then it is highly suggestive of impaired adrenal insufficiency, if neither 11-deoxycortisol nor ACTH rise it is highly suggestive of an impaired HPA axis at either the pituitary or hypothalamus.

Metyrapone test may aid in verifying the cause of Cushing's syndrome. Most patients with pituitary dysfunction and/or pituitary microadenoma will increase ACTH secretion in response to metyrapone, while most ectopic ACTH-producing tumors will not. Pituitary macroadenomas do not always respond to metyrapone.

Experimental use[edit]

Metyrapone has been found in early human trials to reduce recollection of emotional memories in normal volunteers. The volunteers showed significant impairment in ability to retrieve memories with negative emotional content while not impairing memories with neutral content. This has significant implication in the study of the process of emotional healing in post traumatic stress disorder.^[2]^[3]

Due to the permissive action of cortisol on glucagon partial blockade of cortisol may reduce the effects of circulating glucagon in chronically increasing blood glucose in Syndrome X / type 2 diabetes.

References[edit]

^ Young EA, Ribeiro SC, Ye W (June 2007). "Sex Differences in ACTH Pulsatility following Metyrapone Blockade in Patients with Major Depression". Psychoneuroendocrinology 32 (5): 503–7. doi:10.1016/j.psyneuen.2007.03.003. PMC 1975691. PMID 17462829.
^ University of Montreal (27 May 2011). "Drug may help overwrite bad memories". Science Daily (online: ScienceDaily). Retrieved 27 May 2011.
^ Marin, Marie-Frances; A. Hupbach, F. S. Maheu, K. Nader, S. J. Lupien. "Metyrapone Administration Reduces the Strength of an Emotional Memory Trace in a Long-Lasting Manner". Journal of Clinical Endocrinology & Metabolism. early release abstract (8): E1221. doi:10.1210/jc.2011-0226. Cite uses deprecated parameters (help)

External links[edit]

Huffington Post reports that Metyrapone may someday by used to manage PTSD by weakening those bad memories while keeping the good ones strong.

UpToDate Contents

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1. メチラポン刺激試験 metyrapone stimulation tests
2. 副腎皮質機能亢進症の内科的治療（クッシング症候群） medical therapy of hypercortisolism cushings syndrome
3. 成人における副腎不全の診断 diagnosis of adrenal insufficiency in adults
4. 下垂体機能低下症の診断 diagnosis of hypopituitarism
5. 副腎酵素阻害剤および抗アドレナリン薬の薬理および毒性 pharmacology and toxicity of adrenal enzyme inhibitors and adrenolytic agents

English Journal

Novel Imidazol-1-ylmethyl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as Potent and Selective CYP11B1 Inhibitors for the Treatment of Cushing's Syndrome.

Yin L, Lucas S, Maurer F, Kazmaier U, Hu Q, Hartmann RW.SourcePharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrücken, Germany.
Journal of medicinal chemistry.J Med Chem.2012 Jul 26;55(14):6629-33. Epub 2012 Jul 12.
CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC(50) = 2.2 nM) than leads and more selective (SF = 11) than I
PMID 22788843

Screening for modulatory effects on steroidogenesis using the human H295R adrenocortical cell line: a metabolomics approach.

Rijk JC, Peijnenburg AA, Blokland MH, Lommen A, Hoogenboom LR, Bovee T.AbstractThe recently OECD validated H295R steroidogenesis assay provides an in vitro alternative to evaluate the potential interference of exogenous compounds with endogenous steroid hormone synthesis. Currently this assay is used for a simple 'negative-positive' screening of compounds using testosterone and estradiol levels as endpoints, measured with specific enzyme immunoassays (EIAs) or targeted liquid chromatography (LC) and gas chromatography (GC) mass spectrometry (MS) methods. However, recent developments in LC-MS and bioinformatics allow more comprehensive approaches to evaluate changes in steroid profiles. In the current work, the H295R cell model was combined with a metabolomics approach to monitor changes in metabolite profiles in both a targeted and untargeted way. H295R cells were exposed for 48 hours to model compounds, i.e. forskolin, abiraterone, prochloraz, ketoconazole, trilostane, formestane, aminoglutethimide, fadrozole, etomidate and metyrapone, known to affect steroidogenesis. After exposure, the levels of 9 natural steroids were determined by a quantitative targeted GC-MS/MS method and compared to a metabolomics method using Ultra Performance Liquid Chromatography Time-Of-Flight Mass Spectrometry (UPLC-ToF-MS). Like the EIAs, both methods were suited for 'negative-positive' screening, but the MS methods also generated specific fingerprints, allowing chemical class prediction of the compound under investigation. Although the targeted GC-MS/MS was more sensitive, which was an advantage regarding analysis of the estrogens 17ß-estradiol and estrone, the untargeted UPLC-ToF-MS was able to evaluate effects on the synthesis of the corticosteroids. Moreover, untargeted comparison of the aligned chemical profiles allowed identification of all signals that are differential between exposed and non-exposed H295R cells. In conclusion, application of a comprehensive metabolite profiling methodology not only provides a tool to screen compounds for steroidogenic modulating properties, but also allows chemical class prediction. As such, steroid profiling methodologies in conjunction with the H295R assay can contribute to the prioritization of chemicals for additional safety testing.
Chemical research in toxicology.Chem Res Toxicol.2012 Jul 6. [Epub ahead of print]
The recently OECD validated H295R steroidogenesis assay provides an in vitro alternative to evaluate the potential interference of exogenous compounds with endogenous steroid hormone synthesis. Currently this assay is used for a simple 'negative-positive' screening of compounds using testosterone an
PMID 22768806

Japanese Journal

Effects of Cortisol on Pregnancy Rate and Corpus Luteum Function in Heifers : An In Vivo Study

DUONG Hai Thanh,PIOTROWSKA-TOMALA Katarzyna Karolina,ACOSTA Tomas Javier [他],BAH Mamadou Mousa,SINDEREWICZ Emilia,MAJEWSKA Magdalena,JANKOWSKA Katarzynna,OKUDA Kiyoshi,SKARZYNSKI Dariusz Jan
The Journal of reproduction and development 58(2), 223-230, 2012-04-01
… In preliminary experiments, doses of cortisol and metyrapone (an inhibitor of cortisol synthesis) were established (n=33). … Metyrapone in effective doses of 500 mg increased the P4 concentration. … Moreover, metyrapone increased P4 and prolonged the CL lifespan in comparison to control animals (P<0.05). …
NAID 10030753904

副腎腫瘍の治療薬物治療 Cushing症候群 (内分泌腺腫瘍--基礎・臨床研究のアップデート) -- (副腎腫瘍)

飯野和美,沖隆
日本臨床 69(-) (995), 550-554, 2011-03
NAID 40018749433

Clinical features and management of ectopic ACTH syndrome at a single institute in Japan

DOI Masaru,SUGIYAMA Toru,IZUMIYAMA Hajime,YOSHIMOTO Takanobu,HIRATA Yukio
Endocrine journal 57(12), 1061-1069, 2010-12-01
NAID 10029587142

Related Pictures

★リンクテーブル★

リンク元	「メチラポン」「METOPIRONE」

「メチラポン」

Metyrapone
Systematic (IUPAC) name
	2-methyl-1,2-di(pyridin-3-yl)propan-1-one
Clinical data
Trade names	Metopirone
AHFS/Drugs.com	Consumer Drug Information
Pregnancy cat.	C US
Legal status	?
Routes	Oral
Pharmacokinetic data
Half-life	1.9 ±0.7 hours.
Identifiers
CAS number	54-36-4
ATC code	V04CD01
PubChem	CID 4174
DrugBank	DB01011
ChemSpider	4030
UNII	ZS9KD92H6V
KEGG	D00410
ChEBI	CHEBI:44241
ChEMBL	CHEMBL934
Chemical data
Formula	C14H14N2O
Mol. mass	226.274 g/mol
	SMILES O=C(c1cccnc1)C(c2cccnc2)(C)C;
	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 ; Key:FJLBFSROUSIWMA-UHFFFAOYSA-N ;
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英: metyrapone
商: メトロピン METOPIRONE
関: メチラポン負荷試験、糖質コルチコイド、副腎皮質

概念

下垂体機能検査薬。下垂体ACTH分泌予備能の検査薬。
副腎でのコルチゾール産生を阻害する。

薬理作用

11β-hydroxylase阻害作用