An inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is used to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma. (Martindale, The Extra Pharmacopoeia, 30th ed)

Structure

Similar Structures

Synonyms

(-)-alpha-Methyl-L-tyrosine
(–)-α-methyl-L-tyrosine
(S)-alpha-Methyltyrosine
Methyltyrosine
Metirosin
Metirosina
Métirosine
Metirosine
Metirosinum
Metyrosine
α-methyl-L-p-tyrosine
α-methyl-p-tyrosine
α-methyl-para-tyrosine
α-MPT

External IDs

357 O / L 588 / L 588357-0 / L-588357-0 / MK 781 / MK-781

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Demser	Capsule	250 mg/1	Oral	Bausch Health Americas Inc.	1979-10-03	Not applicable
Demser	Capsule	250 mg/1	Oral	Merck Sharp & Dohme Limited	1979-10-03	2009-05-31

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

UNII

DOQ0J0TPF7

CAS number

672-87-7

Weight

Average: 195.2151
Monoisotopic: 195.089543287

Chemical Formula

C₁₀H₁₃NO₃

InChI Key

NHTGHBARYWONDQ-JTQLQIEISA-N

InChI

InChI=1S/C10H13NO3/c1-10(11,9(13)14)6-7-2-4-8(12)5-3-7/h2-5,12H,6,11H2,1H3,(H,13,14)/t10-/m0/s1

IUPAC Name

(2S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid

SMILES

C[C@](N)(CC1=CC=C(O)C=C1)C(O)=O

Pharmacology

Indication

For use in the treatment of patients with pheochromocytoma, for preoperative preparation of patients for surgery, management of patients when surgery is contraindicated, and chronic treatment of patients with malignant pheochromocytoma.

Associated Conditions

Pheochromocytomas

Pharmacodynamics

In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of metyrosine per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after metyrosine is discontinued. Most patients with pheochromocytoma treated with metyrosine experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with metyrosine; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.

Mechanism of action

Metyrosine inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines and their synthesis. This consequently, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in the body,usually measured as decreased urinary excretion of catecholamines and their metabolites. One main end result of the catecholamine depletion is a decrease in blood presure.

Target	Actions	Organism
ATyrosine 3-monooxygenase	binder	Humans

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Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

Well absorbed from the gastrointestinal tract.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Little biotransformation, with catechol metabolites accounting for less than 1% of the administered dose.

Route of elimination

Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites.

Half life

3.4 to 3.7 hours

Clearance

Not Available

Toxicity

Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages. At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth. The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid	1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may decrease the antihypertensive activities of Metyrosine.
1-benzylimidazole	1-benzylimidazole may decrease the antihypertensive activities of Metyrosine.
2,5-Dimethoxy-4-ethylamphetamine	2,5-Dimethoxy-4-ethylamphetamine may decrease the antihypertensive activities of Metyrosine.
2,5-Dimethoxy-4-ethylthioamphetamine	2,5-Dimethoxy-4-ethylthioamphetamine may increase the sedative activities of Metyrosine.
4-Bromo-2,5-dimethoxyamphetamine	4-Bromo-2,5-dimethoxyamphetamine may increase the sedative activities of Metyrosine.
4-Methoxyamphetamine	4-Methoxyamphetamine may increase the sedative activities of Metyrosine.
5-methoxy-N,N-dimethyltryptamine	5-methoxy-N,N-dimethyltryptamine may increase the sedative activities of Metyrosine.
7-Nitroindazole	7-Nitroindazole may increase the sedative activities of Metyrosine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline	7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the sedative activities of Metyrosine.
Abediterol	Abediterol may decrease the antihypertensive activities of Metyrosine.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

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Action

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Food Interactions

Not Available

References

Synthesis Reference

US2868818

General References

Not Available

External Links

Human Metabolome Database: HMDB0014903
KEGG Drug: D00762
KEGG Compound: C07921
PubChem Compound: 441350
PubChem Substance: 46506079
ChemSpider: 390103
ChEBI: 6912
ChEMBL: CHEMBL1200862
Therapeutic Targets Database: DAP000471
PharmGKB: PA450487
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Metyrosine

ATC Codes

C02KB01 — Metirosine

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Not Yet Recruiting	Treatment	Ewing's Sarcoma (ES) / Sarcomas	1
2	Terminated	Treatment	Psychosis / Velo-Cardio-Facial Syndrome	1
3	Enrolling by Invitation	Treatment	Autonomic Nervous System Diseases / Dopamine Beta-Hydroxylase Deficiency / Orthostatic Hypotension / Orthostatic Intolerance	1
Not Available	Suspended	Diagnostic	Bulimia Nervosa (BN) / Catechol-O-methyltransferase / Dopamine / Eating Disorders / Reward	1

Pharmacoeconomics

Manufacturers

Aton pharma inc

Packagers

Aton Pharma Inc.
Draxis Specialty Pharmaceuticals Inc.
Merck & Co.

Dosage forms

Form	Route	Strength
Capsule	Oral	250 mg/1

Prices

Unit description	Cost	Unit
Demser 250 mg capsule	19.35USD	capsule

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	312.5 °C	PhysProp
water solubility	Very slightly soluble	Not Available
logP	-1.7	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	2.48 mg/mL	ALOGPS
logP	-1.9	ALOGPS
logP	-1.1	ChemAxon
logS	-1.9	ALOGPS
pKa (Strongest Acidic)	2.06	ChemAxon
pKa (Strongest Basic)	9.93	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	83.55 Å²	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	51.81 m³·mol^-1	ChemAxon
Polarizability	19.9 Å³	ChemAxon
Number of Rings	1	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.9918
Blood Brain Barrier	-	0.8678
Caco-2 permeable	-	0.7026
P-glycoprotein substrate	Substrate	0.5286
P-glycoprotein inhibitor I	Non-inhibitor	0.9891
P-glycoprotein inhibitor II	Non-inhibitor	0.9926
Renal organic cation transporter	Non-inhibitor	0.9278
CYP450 2C9 substrate	Non-substrate	0.8025
CYP450 2D6 substrate	Non-substrate	0.7432
CYP450 3A4 substrate	Non-substrate	0.6887
CYP450 1A2 substrate	Non-inhibitor	0.9459
CYP450 2C9 inhibitor	Non-inhibitor	0.951
CYP450 2D6 inhibitor	Non-inhibitor	0.9574
CYP450 2C19 inhibitor	Non-inhibitor	0.9116
CYP450 3A4 inhibitor	Non-inhibitor	0.892
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9735
Ames test	Non AMES toxic	0.9695
Carcinogenicity	Non-carcinogens	0.8681
Biodegradation	Not ready biodegradable	0.7891
Rat acute toxicity	2.1516 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9852
hERG inhibition (predictor II)	Non-inhibitor	0.9728

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Taxonomy

Description: This compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.
Kingdom: Organic compounds
Super Class: Phenylpropanoids and polyketides
Class: Phenylpropanoic acids
Sub Class: Not Available
Direct Parent: Phenylpropanoic acids
Alternative Parents: D-alpha-amino acids / Amphetamines and derivatives / Phenylpropanes / Aralkylamines / 1-hydroxy-2-unsubstituted benzenoids / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organic oxides
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Substituents: 3-phenylpropanoic-acid / Alpha-amino acid / Alpha-amino acid or derivatives / Amphetamine or derivatives / D-alpha-amino acid / Phenylpropane / 1-hydroxy-2-unsubstituted benzenoid / Aralkylamine / Phenol / Monocyclic benzene moiety
show 18 more
Molecular Framework: Aromatic homomonocyclic compounds
External Descriptors: non-proteinogenic L-alpha-amino acid, L-tyrosine derivative (CHEBI:6912)

Targets

Details1. Tyrosine 3-monooxygenase

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Binder

General Function: Tyrosine 3-monooxygenase activity
Specific Function: Plays an important role in the physiology of adrenergic neurons.
Gene Name: TH
Uniprot ID: P07101
Uniprot Name: Tyrosine 3-monooxygenase
Molecular Weight: 58599.545 Da

References

Nasrallah HA, Donnelly EF, Bigelow LB, Rivera-Calimlim L, Rogol A, Potkin S, Rauscher FP, Wyatt RJ: Inhibition of dopamine synthesis in chronic schizophrenia. Clinical ineffectiveness of metyrosine. Arch Gen Psychiatry. 1977 Jun;34(6):649-55. [PubMed:17374]
Yoshimoto Y, Nakaso K, Nakashima K: L-dopa and dopamine enhance the formation of aggregates under proteasome inhibition in PC12 cells. FEBS Lett. 2005 Feb 14;579(5):1197-202. Epub 2005 Jan 21. [PubMed:15710413]
Shore PA, Dorris RL: On a prime role for newly synthesized dopamine in striatal function. Eur J Pharmacol. 1975 Feb;30(2):315-8. [PubMed:1168577]
Moore KE, Demarest KT, Johnston CA: Influence of prolactin on dopaminergic neuronal systems in the hypothalamus. Fed Proc. 1980 Sep;39(11):2912-6. [PubMed:7409209]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2019 00:34

Metyrosine

Identification

Structure for Metyrosine (DB00765)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References