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Identification
NameVigabatrin
Accession NumberDB01080  (APRD00282)
TypeSmall Molecule
GroupsApproved
Description

An analogue of gamma-aminobutyric acid, vigabatrin is an irreversible inhibitor of 4-aminobutyrate transaminase, the enzyme responsible for the catabolism of gamma-aminobutyric acid. (From Martindale The Extra Pharmacopoeia, 31st ed). Off-label uses include treatment of cocaine dependence.

Structure
Thumb
Synonyms
SynonymLanguageCode
4-Amino-5-hexenoic acidNot AvailableNot Available
gamma-Vinyl GABANot AvailableNot Available
gamma-Vinyl-gamma-aminobutyric acidNot AvailableNot Available
GVGNot AvailableNot Available
VigabatrinNot AvailableINN, BAN, USAN
VigabatrinaSpanishNot Available
VigabatrineFrenchNot Available
VigabatrinumLatinNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Sabriltablet, film coated500 mgoralLundbeck LLC2009-08-21Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Sabrilpowder, for solution50 mg/mLoralLundbeck LLC2009-08-21Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Sabriltablet500 mgoralLundbeck LLCNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Sabrilpowder500 mgoralLundbeck LLCNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
Sabrilan Lundbeck Inc.
Sabrilex Lundbeck Inc.
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number60643-86-9
WeightAverage: 129.157
Monoisotopic: 129.078978601
Chemical FormulaC6H11NO2
InChI KeyPJDFLNIOAUIZSL-UHFFFAOYSA-N
InChI
InChI=1S/C6H11NO2/c1-2-5(7)3-4-6(8)9/h2,5H,1,3-4,7H2,(H,8,9)
IUPAC Name
4-aminohex-5-enoic acid
SMILES
NC(CCC(O)=O)C=C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentGamma amino acids and derivatives
Alternative Parents
Substituents
  • Gamma amino acid or derivatives
  • Medium-chain fatty acid
  • Amino fatty acid
  • Fatty acyl
  • Fatty acid
  • Unsaturated fatty acid
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Carbonyl group
  • Amine
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor use as an adjunct in treatment resistant epilepsy, refractory complex partial seizures, and secondary generalized seizures. It is also used as monotherapy in infantile spasms in West syndrome.
PharmacodynamicsVigabatrin is an anticonvulsant chemically unrelated to other anticonvulsants. Vigabatrin prevents the catabolism of GABA by irreversibly inhibiting the enzyme GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. However, vigabatrin is not a potent inhibitor of GABA-T with a Ki of 10 mM.
Mechanism of actionVigabatrin increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by irreversibly inhibiting enzymes that catabolize GABA (gamma-aminobutyric acid transaminase, GABA-T). Duration of action is determined by rate of GABA-T re-synthesis. Vigabatrin may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. Although administered as a racemic mixture, only the S(+) enantiomer is pharmacologically active.
AbsorptionRapidly absorbed following oral administration, absorption is comparable between neonates, infants, and children. Cmax, 50 mg/kg dose, neonates= 14 mg/L; Tmax, 50 mg/kg dose, neonates = 2.1 hours; However, extent of absorption is higher and elimination half life is longer in neonates compared to children and infants. This is because neonates have reduced renal function compared to the aforementioned population groups. AUC, 50 mg/kg dose, neonates = 142.6 ± 44.0 mg/L/hr; Food may slightly decrease the rate (Cmax decreased by 33%, Tmax increased to 2 hours), but not the extent of absorption. Furthermore, vigabatrin does not cross the blood-brain-barrier well, thus high doses are needed.
Volume of distribution

1.1 L/kg

Protein bindingNot protein bound
Metabolism

Almost no metabolic transformation. Does not induce the hepatic cytochrome P450 system.

Route of eliminationEliminated primarily through renal excretion as unchanged drugs (80%).
Half lifeNeonates, 50 mg/kg = 7.5 ± 2.1 hours (due to reduced renal function); Infants = 5.7 hours; Adults = 7.5 hours; Elderly = 12 - 13 hours
Clearance

Infants = 2.4 ± 0.8 L/h;
Children = 5.7 ± 2.5 L/h

ToxicityLD50, oral, rat: 3000 mg/kg; Visual field defects may occur following cumulative doses in excess of 2 kg.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9213
Blood Brain Barrier+0.9382
Caco-2 permeable-0.5191
P-glycoprotein substrateNon-substrate0.797
P-glycoprotein inhibitor INon-inhibitor0.949
P-glycoprotein inhibitor IINon-inhibitor0.9856
Renal organic cation transporterNon-inhibitor0.8944
CYP450 2C9 substrateNon-substrate0.8785
CYP450 2D6 substrateNon-substrate0.8115
CYP450 3A4 substrateNon-substrate0.7664
CYP450 1A2 substrateNon-inhibitor0.9149
CYP450 2C9 substrateNon-inhibitor0.9389
CYP450 2D6 substrateNon-inhibitor0.9654
CYP450 2C19 substrateNon-inhibitor0.963
CYP450 3A4 substrateNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9824
Ames testNon AMES toxic0.8409
CarcinogenicityNon-carcinogens0.7678
BiodegradationReady biodegradable0.7494
Rat acute toxicity1.6656 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9617
hERG inhibition (predictor II)Non-inhibitor0.9772
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Powderoral500 mg
Powder, for solutionoral50 mg/mL
Tabletoral500 mg
Tablet, film coatedoral500 mg
Prices
Unit descriptionCostUnit
Sabril 500 mg tablet16.66USD tablet
Sabril 500 mg Powder Packet0.95USD packet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility55.1 mg/mLNot Available
logP-2.16HENCZI,M ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility96.6 mg/mLALOGPS
logP-2.6ALOGPS
logP-2.1ChemAxon
logS-0.13ALOGPS
pKa (Strongest Acidic)4.61ChemAxon
pKa (Strongest Basic)9.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area63.32 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity34.29 m3·mol-1ChemAxon
Polarizability13.64 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Gram L, Larsson OM, Johnsen A, Schousboe A: Experimental studies of the influence of vigabatrin on the GABA system. Br J Clin Pharmacol. 1989;27 Suppl 1:13S-17S. Pubmed
  2. Browne TR: Pharmacokinetics of antiepileptic drugs. Neurology. 1998 Nov;51(5 Suppl 4):S2-7. Pubmed
  3. Lindberger M, Luhr O, Johannessen SI, Larsson S, Tomson T: Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit. 2003 Aug;25(4):457-62. Pubmed
  4. Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ, Rupprecht R: Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology. 2001 Nov;25(5):699-703. Pubmed
  5. Tulloch JK, Carr RR, Ensom MH: A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther. 2012 Jan;17(1):31-44. doi: 10.5863/1551-6776-17.1.31. Pubmed
  6. Clayton LM, Stern WM, Newman WD, Sander JW, Acheson J, Sisodiya SM: Evolution of visual field loss over ten years in individuals taking vigabatrin. Epilepsy Res. 2013 Mar 28. pii: S0920-1211(13)00074-0. doi: 10.1016/j.eplepsyres.2013.02.014. Pubmed
  7. Hawker DD, Silverman RB: Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase. Bioorg Med Chem. 2012 Oct 1;20(19):5763-73. doi: 10.1016/j.bmc.2012.08.009. Epub 2012 Aug 16. Pubmed
External Links
ATC CodesN03AG04
AHFS Codes
  • 28:12.92
PDB Entries
FDA labelDownload (307 KB)
MSDSDownload (63.9 KB)
Interactions
Drug Interactions
Drug
BuprenorphineCNS Depressants may enhance the CNS depressant effect of Buprenorphine.
ClonazepamMay enhance the CNS depressant effect of ClonazePAM. Vigabatrin may increase the serum concentration of ClonazePAM.
DoxylamineMay enhance the CNS depressant effect of CNS Depressants.
DronabinolMay enhance the CNS depressant effect of CNS Depressants.
DroperidolMay enhance the CNS depressant effect of CNS Depressants.
FosphenytoinVigabatrin may decrease the serum concentration of Fosphenytoin.
HydrocodoneCNS Depressants may enhance the CNS depressant effect of Hydrocodone.
HydroxyzineMay enhance the CNS depressant effect of CNS Depressants.
Magnesium SulfateMay enhance the CNS depressant effect of CNS Depressants.
MefloquineMefloquine may diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants.
MethotrimeprazineCNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.
MetyrosineCNS Depressants may enhance the sedative effect of Metyrosine.
MianserinMay diminish the therapeutic effect of Anticonvulsants.
MirtazapineCNS Depressants may enhance the CNS depressant effect of Mirtazapine.
NabiloneMay enhance the CNS depressant effect of CNS Depressants.
OrlistatMay decrease the serum concentration of Anticonvulsants.
OrphenadrineCNS Depressants may enhance the CNS depressant effect of Orphenadrine.
PerampanelMay enhance the CNS depressant effect of CNS Depressants.
PhenytoinMay decrease the serum concentration of Phenytoin.
PramipexoleCNS Depressants may enhance the sedative effect of Pramipexole.
RopiniroleCNS Depressants may enhance the sedative effect of ROPINIRole.
RotigotineCNS Depressants may enhance the sedative effect of Rotigotine.
RufinamideMay enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
SuvorexantCNS Depressants may enhance the CNS depressant effect of Suvorexant.
TapentadolMay enhance the CNS depressant effect of CNS Depressants.
ThalidomideCNS Depressants may enhance the CNS depressant effect of Thalidomide.
ZolpidemCNS Depressants may enhance the CNS depressant effect of Zolpidem.
Food InteractionsNot Available

Targets

1. Gamma-aminobutyric acid type B receptor subunit 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid type B receptor subunit 1 Q9UBS5 Details

References:

  1. Tyacke RJ, Lingford-Hughes A, Reed LJ, Nutt DJ: GABAB receptors in addiction and its treatment. Adv Pharmacol. 2010;58:373-96. Pubmed

2. 4-aminobutyrate aminotransferase, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
4-aminobutyrate aminotransferase, mitochondrial P80404 Details

References:

  1. Weber OM, Verhagen A, Duc CO, Meier D, Leenders KL, Boesiger P: Effects of vigabatrin intake on brain GABA activity as monitored by spectrally edited magnetic resonance spectroscopy and positron emission tomography. Magn Reson Imaging. 1999 Apr;17(3):417-25. Pubmed
  2. Valdizan EM, Garcia AP, Armijo JA: Effects of increasing doses of vigabatrin on platelet gamma-aminobutyric acid-transaminase and brain gamma-aminobutyric acid in rats. Eur J Pharmacol. 1999 Mar 19;369(2):169-73. Pubmed
  3. Arndt CF, Derambure P, Defoort-Dhellemmes S, Hache JC: Outer retinal dysfunction in patients treated with vigabatrin. Neurology. 1999 Apr 12;52(6):1201-5. Pubmed
  4. Molina PE, Ahmed N, Ajmal M, Dewey S, Volkow N, Fowler J, Abumrad N: Co-administration of gamma-vinyl GABA and cocaine: preclinical assessment of safety. Life Sci. 1999;65(11):1175-82. Pubmed
  5. French JA: Vigabatrin. Epilepsia. 1999;40 Suppl 5:S11-6. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Transporters

1. Proton-coupled amino acid transporter 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Proton-coupled amino acid transporter 1 Q7Z2H8 Details

References:

  1. Abbot EL, Grenade DS, Kennedy DJ, Gatfield KM, Thwaites DT: Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+ -coupled amino-acid transporter hPAT1. Br J Pharmacol. 2006 Feb;147(3):298-306. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13