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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
SaltsNot Available
Brand names
NameCompany
SabrilLundbeck Inc.
Sabrilan Lundbeck Inc.
Sabrilex Lundbeck Inc.
Brand mixturesNot 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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentGamma Amino Acids and Derivatives
Alternative parentsAmino Fatty Acids; Unsaturated Fatty Acids; Polyamines; Carboxylic Acids; Enolates; Monoalkylamines
Substituentscarboxylic acid; enolate; polyamine; primary amine; amine; primary aliphatic amine; organonitrogen compound
Classification descriptionThis compound belongs to the gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
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
Property Value Probability
Human Intestinal Absorption + 0.9213
Blood Brain Barrier + 0.9382
Caco-2 permeable - 0.5191
P-glycoprotein substrate Non-substrate 0.797
P-glycoprotein inhibitor I Non-inhibitor 0.949
P-glycoprotein inhibitor II Non-inhibitor 0.9856
Renal organic cation transporter Non-inhibitor 0.8944
CYP450 2C9 substrate Non-substrate 0.8785
CYP450 2D6 substrate Non-substrate 0.8115
CYP450 3A4 substrate Non-substrate 0.7664
CYP450 1A2 substrate Non-inhibitor 0.9149
CYP450 2C9 substrate Non-inhibitor 0.9389
CYP450 2D6 substrate Non-inhibitor 0.9654
CYP450 2C19 substrate Non-inhibitor 0.963
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9824
Ames test Non AMES toxic 0.8409
Carcinogenicity Non-carcinogens 0.7678
Biodegradation Ready biodegradable 0.7494
Rat acute toxicity 1.6656 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9617
hERG inhibition (predictor II) Non-inhibitor 0.9772
Pharmacoeconomics
Manufacturers
  • Lundbeck inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionOral500 mg/packet
Powder, for suspensionOral0.5 g/sachet
TabletOral500 mg
Prices
Unit descriptionCostUnit
Sabril 500 mg tablet16.66USDtablet
Sabril 500 mg Powder Packet0.95USDpacket
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 solubility9.66e+01 g/lALOGPS
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 area63.32ChemAxon
rotatable bond count4ChemAxon
refractivity34.29ChemAxon
polarizability13.64ChemAxon
number of rings0ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
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
ResourceLink
KEGG DrugD00535
KEGG CompoundC07500
PubChem Compound5665
PubChem Substance46507052
ChemSpider5463
BindingDB50118886
Therapeutic Targets DatabaseDAP000557
PharmGKBPA10231
Drug Product Database2068036
RxListhttp://www.rxlist.com/sabril-drug.htm
Drugs.comhttp://www.drugs.com/cdi/vigabatrin.html
WikipediaVigabatrin
ATC CodesN03AG04
AHFS Codes
  • 28:12.92
PDB Entries
FDA labelshow(307 KB)
MSDSshow(63.9 KB)
Interactions
Drug Interactions
Drug
ClonazepamVigabatrin increases Cmax of clonazepam by 30% and decreases Tmax by 45%
FosphenytoinVigabatrin decreases the effect of hydantoin
MefloquineMefloquine may decrease the serum concentration of Vigabatrin. This may increase the risk of seizure in patients receiving Vigabatrin to prevent seizures. Consider alternate therapy or monitor for changes in Vigabatrin serum concentration, therapeutic or adverse effects if Mefloquin is initiated, discontinued or dose changed.
MethotrimeprazineAdditive CNS depression may occur. Dose adjustments may be required if one agent is added to existing therapy with the other agent. Monitor for increased CNS depression during concomitant therapy.
PhenobarbitalVigabatrin reduces serum concentrations of phenobarbital by 8-16%.
PhenytoinVigabatrin reduces plasma levels of phenytoin by 16-20% which may be due to induction of CYP2C. Consider dosage adjustment.
SildenafilIncreased anticonvulsant effects of vigabatrin due to pharmacodynamic synergism. Monitor for adverse effects during concomitant therapy.
TriprolidineThe CNS depressants, Triprolidine and Vigabatrin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Valproic AcidVigabatrin reduces serum concentrations of valproic acid by 8%.
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