Metyrosine

Identification

Summary

Metyrosine is a tyrosine 3-monooxygenase inhibitor used to treat excessive sympathetic stimulation in pheochromocytoma.

Brand Names
Demser
Generic Name
Metyrosine
DrugBank Accession Number
DB00765
Background

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)

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 195.2151
Monoisotopic: 195.089543287
Chemical Formula
C10H13NO3
Synonyms
  • (-)-alpha-Methyl-L-tyrosine
  • (–)-α-methyl-L-tyrosine
  • (S)-alpha-Methyltyrosine
  • Methyltyrosine
  • Metirosin
  • Metirosina
  • Metirosine
  • Métirosine
  • 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

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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofPheochromocytoma••••••••••••
Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
ATyrosine 3-monooxygenase
binder
Humans
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

Adverse Effects
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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.

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.
DrugInteraction
1,2-Benzodiazepine1,2-Benzodiazepine may increase the sedative activities of Metyrosine.
AbaloparatideAbaloparatide may increase the hypotensive activities of Metyrosine.
AcebutololMetyrosine may increase the hypotensive activities of Acebutolol.
AceclofenacThe therapeutic efficacy of Metyrosine can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Metyrosine can be decreased when used in combination with Acemetacin.
Food Interactions
  • Avoid alcohol. Ingesting alcohol may increase the sedative and CNS depressant effects of metyrosine.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DemserCapsule250 mg/1OralBausch Health US, LLC1979-10-03Not applicableUS flag
DemserCapsule250 mg/1OralMerck Sharp & Dohme Limited1979-10-032009-05-31US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MetyrosineCapsule250 mg/1OralOceanside Pharmaceuticals2020-09-07Not applicableUS flag
MetyrosineCapsule250 mg/1OralAmneal Pharmaceuticals NY LLC2020-07-24Not applicableUS flag
MetyrosineCapsule250 mg/1OralAmneal Pharmaceuticals NY LLC2020-07-24Not applicableUS flag

Categories

ATC Codes
C02KB01 — Metirosine
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
1-hydroxy-2-unsubstituted benzenoid / 3-phenylpropanoic-acid / Alpha-amino acid / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Amphetamine or derivatives / Aralkylamine / Aromatic homomonocyclic compound
show 18 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
non-proteinogenic L-alpha-amino acid, L-tyrosine derivative (CHEBI:6912)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
DOQ0J0TPF7
CAS number
672-87-7
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

References

Synthesis Reference
US2868818
General References
Not Available
Human Metabolome Database
HMDB0014903
KEGG Drug
D00762
KEGG Compound
C07921
PubChem Compound
441350
PubChem Substance
46506079
ChemSpider
390103
RxNav
266604
ChEBI
6912
ChEMBL
CHEMBL1200862
ZINC
ZINC000000000693
Therapeutic Targets Database
DAP000471
PharmGKB
PA450487
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
%CE%91-Methyl-p-tyrosine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentEwing's Sarcoma / Sarcomas1
2TerminatedTreatmentPsychosis / Velo-Cardio-Facial Syndrome1
Not AvailableSuspendedDiagnosticBulimia Nervosa / Catechol-O-methyltransferase / Dopamine / Eating Disorders / Reward1

Pharmacoeconomics

Manufacturers
  • Aton pharma inc
Packagers
  • Aton Pharma Inc.
  • Draxis Specialty Pharmaceuticals Inc.
  • Merck & Co.
Dosage Forms
FormRouteStrength
CapsuleOral250 mg/1
Prices
Unit descriptionCostUnit
Demser 250 mg capsule19.35USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)312.5 °CPhysProp
water solubilityVery slightly solubleNot Available
logP-1.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.48 mg/mLALOGPS
logP-1.9ALOGPS
logP-1.1Chemaxon
logS-1.9ALOGPS
pKa (Strongest Acidic)2.06Chemaxon
pKa (Strongest Basic)9.93Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area83.55 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity51.81 m3·mol-1Chemaxon
Polarizability19.67 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9918
Blood Brain Barrier-0.8678
Caco-2 permeable-0.7026
P-glycoprotein substrateSubstrate0.5286
P-glycoprotein inhibitor INon-inhibitor0.9891
P-glycoprotein inhibitor IINon-inhibitor0.9926
Renal organic cation transporterNon-inhibitor0.9278
CYP450 2C9 substrateNon-substrate0.8025
CYP450 2D6 substrateNon-substrate0.7432
CYP450 3A4 substrateNon-substrate0.6887
CYP450 1A2 substrateNon-inhibitor0.9459
CYP450 2C9 inhibitorNon-inhibitor0.951
CYP450 2D6 inhibitorNon-inhibitor0.9574
CYP450 2C19 inhibitorNon-inhibitor0.9116
CYP450 3A4 inhibitorNon-inhibitor0.892
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9735
Ames testNon AMES toxic0.9695
CarcinogenicityNon-carcinogens0.8681
BiodegradationNot ready biodegradable0.7891
Rat acute toxicity2.1516 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9852
hERG inhibition (predictor II)Non-inhibitor0.9728
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-052f-4900000000-946ec0a9cb27d9dde874
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-0900000000-6652807f813af2805df0
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001u-1900000000-48087192d8178ca8f379
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001l-9600000000-91800dc45fcc61a7e3bb
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-000x-9500000000-12583b60232daa450d7c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-1900000000-6a1d86a47a2c97fa7eca
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-9100000000-127a492975d36ac670ff
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-150.4716534
predicted
DarkChem Lite v0.1.0
[M-H]-149.9081534
predicted
DarkChem Lite v0.1.0
[M-H]-138.17018
predicted
DeepCCS 1.0 (2019)
[M+H]+150.0557534
predicted
DarkChem Lite v0.1.0
[M+H]+150.3057534
predicted
DarkChem Lite v0.1.0
[M+H]+140.56203
predicted
DeepCCS 1.0 (2019)
[M+Na]+150.1769534
predicted
DarkChem Lite v0.1.0
[M+Na]+149.9468534
predicted
DarkChem Lite v0.1.0
[M+Na]+148.10939
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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
  1. 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. [Article]
  2. 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. [Article]
  3. Shore PA, Dorris RL: On a prime role for newly synthesized dopamine in striatal function. Eur J Pharmacol. 1975 Feb;30(2):315-8. [Article]
  4. Moore KE, Demarest KT, Johnston CA: Influence of prolactin on dopaminergic neuronal systems in the hypothalamus. Fed Proc. 1980 Sep;39(11):2912-6. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 02, 2023 06:55