Identification

Name
Tetrabenazine
Accession Number
DB04844
Type
Small Molecule
Groups
Approved, Investigational
Description

A drug formerly used as an antipsychotic but now used primarily in the symptomatic treatment of various hyperkinetic disorders. It is a monoamine depletor and used as symptomatic treatment of chorea associated with Huntington's disease. FDA approved on August 15, 2008.

Structure
Thumb
Synonyms
  • 1,2,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2H-benzo[a]quinolizin-2-one
  • 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine
  • 2-oxo-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-benzoquinolizine
  • Tetrabenazina
  • Tetrabenazinum
External IDs
RO 1-9569 / RO-1-9569 / RO-19569
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NitomanTablet25 mgOralValeant Canada Lp Valeant Canada S.E.C.1996-12-09Not applicableCanada
Tetrabenazine TabletsTablet25 mgOralSterimax Inc2013-08-29Not applicableCanada
XenazineTablet25 mg/1OralLundbeck Pharmaceuticals Llc2008-11-24Not applicableUs
XenazineTablet12.5 mg/1OralLundbeck Pharmaceuticals Llc2008-11-24Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-tetrabenazineTablet25 mgOralApotex Corporation2013-11-01Not applicableCanada
PMS-tetrabenazineTablet25 mgOralPharmascience Inc2013-02-26Not applicableCanada
TetrabenazineTablet25 mg/1OralIngenus Pharmaceuticals Nj, Llc2017-03-01Not applicableUs
TetrabenazineTablet12.5 mg/1OralLupin Pharmaceuticals, Inc.2018-09-25Not applicableUs
TetrabenazineTablet25 mg/1OralDr Reddy's Laboratories2018-01-08Not applicableUs
TetrabenazineTablet25 mg/1OralOceanside Pharmaceuticals2015-07-20Not applicableUs
TetrabenazineTablet, coated12.5 mg/1OralCamber Pharmaceuticals2015-08-17Not applicableUs
TetrabenazineTablet12.5 mg/1OralSun Pharmaceutical Industries, Inc.2015-08-17Not applicableUs
TetrabenazineTablet25 mg/1OralAv Kare, Inc.2017-02-08Not applicableUs
TetrabenazineTablet12.5 mg/1OralIngenus Pharmaceuticals Nj, Llc2017-03-01Not applicableUs
International/Other Brands
Rubigen
Categories
UNII
Z9O08YRN8O
CAS number
58-46-8
Weight
Average: 317.4226
Monoisotopic: 317.199093735
Chemical Formula
C19H27NO3
InChI Key
MKJIEFSOBYUXJB-UHFFFAOYSA-N
InChI
InChI=1S/C19H27NO3/c1-12(2)7-14-11-20-6-5-13-8-18(22-3)19(23-4)9-15(13)16(20)10-17(14)21/h8-9,12,14,16H,5-7,10-11H2,1-4H3
IUPAC Name
9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one
SMILES
COC1=C(OC)C=C2C3CC(=O)C(CC(C)C)CN3CCC2=C1

Pharmacology

Indication

Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia

Associated Conditions
Pharmacodynamics

Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

Mechanism of action

Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).

TargetActionsOrganism
ASynaptic vesicular amine transporter
inhibitor
Human
UD(2) dopamine receptor
inhibitor
Human
Absorption

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients;
Tmax, oral = 69 min in HD or tardive dyskinesia patients

Volume of distribution

Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.

Protein binding

Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%.

Metabolism

Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.

Route of elimination

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose.

Half life

α-HTBZ = 7 hours; β-HTBZ = 5 hours; 9-desmethyl-β-DHTBZ = 12 hours.

Clearance

IV, 1.67 L/min in HD or tardive dyskinesia patients

Toxicity

Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2D6CYP2D6*3Not AvailableC alleleEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*4Not AvailableC alleleEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*5Not AvailableWhole-gene deletionEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*6Not Available1707delTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*7Not Available2935A>CEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*8Not Available1758G>TEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*11Not Available883G>CEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*12Not Available124G>AEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*13Not AvailableCYP2D7/2D6 hybrid gene structureEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*14ANot Available1758G>AEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*15Not Available137insT, 137_138insTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*19Not Available2539_2542delAACTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*20Not Available1973_1974insGEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*21Not Available2573insCEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*31Not Available-1770G>A / -1584C>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*36Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*38Not Available2587_2590delGACTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*40Not Available1863_1864ins(TTT CGC CCC)2Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*42Not Available3259_3260insGTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*44Not Available2950G>CEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*47Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*51Not Available-1584C>G / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*56Not Available3201C>TEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*57Not Available100C>T / 310G>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*62Not Available4044C>TEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*68ANot Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*68BNot AvailableSimilar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*69Not Available2988G>A / -1426C>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*92Not Available1995delCEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*100Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*101Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineThe metabolism of Tetrabenazine can be decreased when combined with 4-Methoxyamphetamine.
AbexinostatThe risk or severity of QTc prolongation can be increased when Abexinostat is combined with Tetrabenazine.
AbirateroneThe metabolism of Tetrabenazine can be decreased when combined with Abiraterone.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Tetrabenazine.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Tetrabenazine.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Tetrabenazine.
AcetaminophenThe metabolism of Tetrabenazine can be decreased when combined with Acetaminophen.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Tetrabenazine.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Acetyldigoxin is combined with Tetrabenazine.
Acetylglycinamide chloral hydrateThe risk or severity of sedation and somnolence can be increased when Acetylglycinamide chloral hydrate is combined with Tetrabenazine.
Food Interactions
Not Available

References

Synthesis Reference

Michael James Rishel, Kande Kankananamalage Dayarathna Amarasinghe, Sean Richard Dinn, Bruce Fletcher Johnson, "METHOD FOR MAKING TETRABENAZINE COMPOUNDS." U.S. Patent US20080306267, issued December 11, 2008.

US20080306267
General References
  1. Jankovic J, Beach J: Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology. 1997 Feb;48(2):358-62. [PubMed:9040721]
  2. Guay DR: Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders. Am J Geriatr Pharmacother. 2010 Aug;8(4):331-73. doi: 10.1016/j.amjopharm.2010.08.006. [PubMed:20869622]
External Links
Human Metabolome Database
HMDB0015592
KEGG Drug
D08575
KEGG Compound
C11168
PubChem Compound
6018
PubChem Substance
46506426
ChemSpider
5796
BindingDB
50017701
ChEBI
64028
ChEMBL
CHEMBL117785
Therapeutic Targets Database
DAP000756
PharmGKB
PA140222719
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tetrabenazine
ATC Codes
N07XX06 — Tetrabenazine
AHFS Codes
  • 28:92.00 — Miscellaneous Central Nervous System Agents
FDA label
Download (456 KB)
MSDS
Download (79.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers2
1RecruitingBasic ScienceHealthy Volunteers1
3CompletedNot AvailableHuntington's Disease (HD)1
3CompletedTreatmentHuntington's Disease (HD)1
3CompletedTreatmentTardive Dyskinesia1
4RecruitingTreatmentHuntington's Disease (HD)1
Not AvailableAvailableNot AvailableHyperkinetic Movement Disorders1
Not AvailableCompletedNot AvailableBipolar Disorder (BD) / Psychotic Disorder NOS / Schizoaffective Disorders / Schizophrenic Disorders / Type 2 Diabetes Mellitus1
Not AvailableCompletedTreatmentSchizoaffective Disorders / Schizophrenic Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Laboratories Fournier Sca
  • Lundbeck Inc.
Dosage forms
FormRouteStrength
TabletOral25 mg
Tablet, coatedOral12.5 mg/1
Tablet, coatedOral25 mg/1
TabletOral12.5 mg/1
TabletOral25 mg/1
Prices
Unit descriptionCostUnit
Xenazine 25 mg tablet74.57USD tablet
Xenazine 12.5 mg tablet37.29USD tablet
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)126 °CMSDS
water solubilitySparingly solubleFDA label
pKa6.51FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.361 mg/mLALOGPS
logP3.23ALOGPS
logP3.4ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)18.24ChemAxon
pKa (Strongest Basic)7.41ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.77 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity91.31 m3·mol-1ChemAxon
Polarizability36.59 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.995
Blood Brain Barrier+0.9639
Caco-2 permeable+0.8608
P-glycoprotein substrateSubstrate0.7819
P-glycoprotein inhibitor IInhibitor0.8908
P-glycoprotein inhibitor IIInhibitor0.7631
Renal organic cation transporterInhibitor0.6484
CYP450 2C9 substrateNon-substrate0.8444
CYP450 2D6 substrateSubstrate0.6448
CYP450 3A4 substrateSubstrate0.8091
CYP450 1A2 substrateNon-inhibitor0.7482
CYP450 2C9 inhibitorNon-inhibitor0.9042
CYP450 2D6 inhibitorInhibitor0.7084
CYP450 2C19 inhibitorNon-inhibitor0.8191
CYP450 3A4 inhibitorNon-inhibitor0.8308
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8718
Ames testNon AMES toxic0.6674
CarcinogenicityNon-carcinogens0.9083
BiodegradationNot ready biodegradable0.9974
Rat acute toxicity2.8540 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6451
hERG inhibition (predictor II)Inhibitor0.7524
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 tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Tetrahydroisoquinolines
Sub Class
Not Available
Direct Parent
Tetrahydroisoquinolines
Alternative Parents
Anisoles / Piperidinones / Aralkylamines / Alkyl aryl ethers / Trialkylamines / Cyclic ketones / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Tetrahydroisoquinoline / Anisole / Alkyl aryl ether / Piperidinone / Aralkylamine / Piperidine / Benzenoid / Ketone / Tertiary amine / Tertiary aliphatic amine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
cyclic ketone, tertiary amino compound, benzoquinolizine (CHEBI:64028)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Monoamine transmembrane transporter activity
Specific Function
Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles...
Gene Name
SLC18A2
Uniprot ID
Q05940
Uniprot Name
Synaptic vesicular amine transporter
Molecular Weight
55712.075 Da
References
  1. Zheng G, Dwoskin LP, Crooks PA: Vesicular monoamine transporter 2: role as a novel target for drug development. AAPS J. 2006 Nov 10;8(4):E682-92. [PubMed:17233532]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  3. Kim YS, Shin JH, Hall FS, Linden DJ: Dopamine signaling is required for depolarization-induced slow current in cerebellar Purkinje cells. J Neurosci. 2009 Jul 1;29(26):8530-8. doi: 10.1523/JNEUROSCI.0468-09.2009. [PubMed:19571144]
  4. Goland R, Freeby M, Parsey R, Saisho Y, Kumar D, Simpson N, Hirsch J, Prince M, Maffei A, Mann JJ, Butler PC, Van Heertum R, Leibel RL, Ichise M, Harris PE: 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls. J Nucl Med. 2009 Mar;50(3):382-9. doi: 10.2967/jnumed.108.054866. Epub 2009 Feb 17. [PubMed:19223416]
  5. Gros Y, Schuldiner S: Directed evolution reveals hidden properties of VMAT, a neurotransmitter transporter. J Biol Chem. 2010 Feb 12;285(7):5076-84. doi: 10.1074/jbc.M109.081216. Epub 2009 Dec 10. [PubMed:20007701]
  6. Wimalasena K: Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev. 2011 Jul;31(4):483-519. doi: 10.1002/med.20187. Epub 2010 Feb 4. [PubMed:20135628]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Poon LH, Kang GA, Lee AJ: Role of tetrabenazine for Huntington's disease-associated chorea. Ann Pharmacother. 2010 Jun;44(6):1080-9. doi: 10.1345/aph.1M582. Epub 2010 May 4. [PubMed:20442355]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-e2 9-reductase activity
Specific Function
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. ...
Gene Name
CBR1
Uniprot ID
P16152
Uniprot Name
Carbonyl reductase [NADPH] 1
Molecular Weight
30374.73 Da
References
  1. Jankovic J, Clarence-Smith K: Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders. Expert Rev Neurother. 2011 Nov;11(11):1509-23. doi: 10.1586/ern.11.149. [PubMed:22014129]

Drug created on October 16, 2007 11:37 / Updated on November 14, 2018 12:53