View source for Metyrapone

{{Short description|Chemical compound}}
{{Distinguish|Metirosine}}
{{Drugbox
| verifiedrevid = 462252001
| IUPAC_name = 2-methyl-1,2-di(pyridin-3-yl)propan-1-one
| image = Metyrapone structure.svg
| width = 225px

<!--Clinical data-->
| tradename = Metopirone
| Drugs.com = {{drugs.com|CDI|metyrapone}}
| pregnancy_category = C <small>[[US]]</small>
| legal_status = 
| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| metabolites = 
| elimination_half-life = 1.9 ± 0.7 hours
| excretion = 

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 54-36-4
| ATC_prefix = V04
| ATC_suffix = CD01
| ATC_supplemental = 
| PubChem = 4174
| IUPHAR_ligand = 5224
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01011
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4030
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = ZS9KD92H6V
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00410
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 44241
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 934

<!--Chemical data-->
| C=14 | H=14 | N=2 | O=1
| SMILES = O=C(c1cccnc1)C(c2cccnc2)(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FJLBFSROUSIWMA-UHFFFAOYSA-N
}}

'''Metyrapone''', sold under the brand name '''Metopirone''', is a medication which is used in the [[diagnosis]] of [[adrenal insufficiency]] and occasionally in the treatment of [[Cushing's syndrome]] (hypercortisolism). It is part of the [[steroidogenesis inhibitor]] class of drugs.

==Medical uses==
Metyrapone can be used in the diagnosis of [[adrenal insufficiency]]. Metyrapone 30&nbsp;mg/kg, maximum dose 3,000&nbsp;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&nbsp;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 remain less than 7&nbsp;μg/dL (202&nbsp;nmol/L) and [[adrenocorticotropic hormone]] (ACTH) rises, then it is highly suggestive of [[adrenal insufficiency]]. If neither 11-deoxycortisol nor ACTH rise, it is highly suggestive of an impaired [[hypothalamic–pituitary–adrenal axis]] at either the [[pituitary]] or [[hypothalamus]].

The 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.

Metyrapone is used for the medical control of hypercortisolism in Cushing's syndrome (ACTH dependent or independent). The aim for medical treatment is to achieve pre-operative control of hypercortisolism, or for control of residual disease persisting post-operatively (TSS, adrenalectomy). It is not for long term definitive treatment/cure, only as an adjunct (surgery is the aim for cure in most causes of Cushing's syndrome). Metyrapone hence acts by inhibiting adrenal steroidogenesis. One side effect is hirsutism (in women) because of the excess androgen precursors created. The other commonly used agent for medical treatment of Cushing's is [[ketoconazole]] (an anti-fungal agent), though it is not FDA approved for Cushing's. This does not exhibit the side effect of hirsutism, but does carry a high risk of hepatoxicity and other serious side effects. [[Levoketoconazole]], an enantiomeric form of ketoconazole, is FDA approved to treat Cushing's and carries a lower risk of hepatoxicity and other serious side effects compared to ketoconazole.

==Pharmacology==

===Pharmacodynamics===
Metyrapone blocks [[cortisol]] [[steroidogenesis]] by acting as a [[reversible inhibitor]] of [[steroid 11β-hydroxylase|11β-hydroxylase]].<ref name="pmid17462829">{{cite journal | vauthors = Young EA, Ribeiro SC, Ye W | title = Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression | journal = Psychoneuroendocrinology | volume = 32 | issue = 5 | pages = 503–507 | date = June 2007 | pmid = 17462829 | pmc = 1975691 | doi = 10.1016/j.psyneuen.2007.03.003 }}</ref> This stimulates [[adrenocorticotropic hormone]] (ACTH) [[secretion]], which in turn increases [[blood plasma|plasma]] [[11-deoxycortisol]] levels.

==Chemistry==
[[Structural analog|Analogue]]s of metyrapone include [[aminoglutethimide]], [[amphenone B]], and [[mitotane]].

==Research==
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]].<ref>{{Cite news | last = University of Montreal| title = Drug may help overwrite bad memories| newspaper = Science Daily| location = online| publisher = ScienceDaily| date = 27 May 2011 | url = https://www.sciencedaily.com/releases/2011/05/110526064802.htm | access-date = 27 May 2011}}</ref><ref>{{cite journal | vauthors = Marin MF, Hupbach A, Maheu FS, Nader K, Lupien SJ | title = Metyrapone administration reduces the strength of an emotional memory trace in a long-lasting manner | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 8 | pages = E1221–E1227 | date = August 2011 | pmid = 21593118 | doi = 10.1210/jc.2011-0226 | doi-access = free }}
</ref>

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 [[metabolic syndrome]] (syndrome X) and [[type 2 diabetes]].

== See also ==
* [[ACTH stimulation test]]

== References ==
{{Reflist}}

{{Diagnostic agents}}
{{Glucocorticoids and antiglucocorticoids}}
{{Glucocorticoid receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}

[[Category:3β-Hydroxysteroid dehydrogenase inhibitors]]
[[Category:11β-Hydroxylase inhibitors]]
[[Category:21-Hydroxylase inhibitors]]
[[Category:CYP2A6 inhibitors]]
[[Category:Antiglucocorticoids]]
[[Category:3-Pyridyl compounds]]