Identification

Name
Metyrosine
Accession Number
DB00765  (APRD01112)
Type
Small Molecule
Groups
Approved
Description

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
Thumb
Synonyms
  • (-)-alpha-Methyl-L-tyrosine
  • (–)-α-methyl-L-tyrosine
  • (S)-alpha-Methyltyrosine
  • Methyltyrosine
  • Metirosin
  • Metirosina
  • Métirosine
  • Metirosine
  • Metirosinum
  • 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
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DemserCapsule250 mg/1OralMerck Sharp & Dohme Limited1979-10-032009-05-31Us
DemserCapsule250 mg/1OralAton Pharma, Inc.1979-10-03Not applicableUs
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
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
Human
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
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidMetyrosine may increase the hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may increase the sedative activities of Metyrosine.
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may increase the sedative activities of Metyrosine.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may increase the sedative activities of Metyrosine.
4-Methoxyamphetamine4-Methoxyamphetamine may increase the sedative activities of Metyrosine.
5-methoxy-N,N-dimethyltryptamine5-methoxy-N,N-dimethyltryptamine may increase the sedative activities of Metyrosine.
7-Nitroindazole7-Nitroindazole may increase the sedative 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
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
PhaseStatusPurposeConditionsCount
2TerminatedTreatmentPsychosis / Velo-Cardio-Facial Syndrome1
3Enrolling by InvitationTreatmentAutonomic Nervous System Diseases / Dopamine Beta-Hydroxylase Deficiency / Idiopathic orthostatic hypotension / Orthostatic Intolerance1
Not AvailableSuspendedDiagnosticBulimia Nervosa (BN) / 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
Polarizability19.9 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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot 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
show 3 more
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

Kind
Protein
Organism
Human
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. [PubMed:17374]
  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. [PubMed:15710413]
  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. [PubMed:1168577]
  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. [PubMed:7409209]
  5. 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, 2018 04:50