Identification

Name
Vigabatrin
Accession Number
DB01080  (APRD00282)
Type
Small Molecule
Groups
Approved
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
  • 4-Amino-5-hexenoic acid
  • Gamma vinyl GABA
  • gamma-Vinyl GABA
  • gamma-Vinyl-gamma-aminobutyric acid
  • GVG
  • Vigabatrin
  • Vigabatrina
  • Vigabatrine
  • Vigabatrinum
  • Vinyl gamma-aminobutyric acid
External IDs
CPP-109 / MDL 71,754 / MDL-71754 / RMI-71754
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SabrilTablet500 mgOralLundbeck Inc.1994-12-31Not applicableCanada
SabrilPowder, for solution50 mg/1mLOralLundbeck Pharmaceuticals Llc2009-08-21Not applicableUs
SabrilPowder500 mgOralLundbeck Inc.1997-08-20Not applicableCanada
SabrilTablet, film coated500 mg/1OralLundbeck Pharmaceuticals Llc2009-08-21Not applicableUs
Sabril Pwr 1g/sachetPowder1 gOralAventis Pharma Ltd.Not applicableNot applicableCanada
Sabril Pwr 2g/sachetPowder2 gOralAventis Pharma Ltd.Not applicableNot applicableCanada
Sabril Pwr 3g/sachetPowder3 gOralAventis Pharma Ltd.Not applicableNot applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VigabatrinPowder, for solution50 mg/1mLOralPar Pharmaceutical2017-04-27Not applicableUs
VigabatrinFor solution500 mg/1OralAmneal Pharmaceuticals LLC2018-03-19Not applicableUs
VigadronePowder, for solution50 mg/1mLOralUpsher-Smith Laboratories, LLC2018-06-21Not applicableUs
International/Other Brands
Sabrilan (Lundbeck Inc. ) / Sabrilex (Lundbeck Inc. )
Categories
UNII
GR120KRT6K
CAS number
68506-86-5
Weight
Average: 129.157
Monoisotopic: 129.078978601
Chemical Formula
C6H11NO2
InChI Key
PJDFLNIOAUIZSL-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

Pharmacology

Indication

For 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.

Associated Conditions
Pharmacodynamics

Vigabatrin 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 action

Vigabatrin 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.

TargetActionsOrganism
AGamma-aminobutyric acid type B receptor subunit 1
agonist
Human
A4-aminobutyrate aminotransferase, mitochondrial
inhibitor
Human
Absorption

Rapidly 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 binding

Not protein bound

Metabolism

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

Route of elimination

Eliminated primarily through renal excretion as unchanged drugs (80%).

Half life

Neonates, 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

Toxicity

LD50, oral, rat: 3000 mg/kg; Visual field defects may occur following cumulative doses in excess of 2 kg.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Vigabatrin.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Vigabatrin is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineVigabatrin may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Vigabatrin is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Vigabatrin is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Vigabatrin is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Vigabatrin is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanineVigabatrin may increase the excretion rate of 6-O-benzylguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-DeazaguanineVigabatrin may increase the excretion rate of 7-Deazaguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Vigabatrin is combined with 7-Nitroindazole.
Food Interactions
Not Available

References

General References
  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:2757904]
  2. Browne TR: Pharmacokinetics of antiepileptic drugs. Neurology. 1998 Nov;51(5 Suppl 4):S2-7. [PubMed:9818917]
  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:12883229]
  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:11682253]
  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:23118657]
  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 Aug;105(3):262-71. doi: 10.1016/j.eplepsyres.2013.02.014. Epub 2013 Mar 28. [PubMed:23541931]
  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:22944334]
External Links
Human Metabolome Database
HMDB0015212
KEGG Drug
D00535
KEGG Compound
C07500
PubChem Compound
5665
PubChem Substance
46507052
ChemSpider
5463
BindingDB
50118886
ChEBI
63638
ChEMBL
CHEMBL89598
Therapeutic Targets Database
DAP000557
PharmGKB
PA10231
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Vigabatrin
ATC Codes
N03AG04 — Vigabatrin
AHFS Codes
  • 28:12.92 — Miscellaneous Anticonvulsants
FDA label
Download (307 KB)
MSDS
Download (63.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceDependence, Cocaine1
1CompletedOtherMethamphetamine Addiction1
1, 2CompletedTreatmentTourette's Disorder1
2CompletedTreatmentDependence, Cocaine2
2RecruitingPreventionTuberous Sclerosis Complex (TSC)1
2TerminatedTreatmentAlcohol Dependence / Dependence, Cocaine1
2TerminatedTreatmentDependence, Cocaine1
2TerminatedTreatmentMethamphetamine Dependence1
2, 3CompletedTreatmentDependence, Cocaine1
3Enrolling by InvitationTreatmentCosyntropin / Infantile Spasm / Vigabatrin1
3RecruitingTreatmentInfantile Spasm1
3RecruitingTreatmentInfantile Spasms (IS)1
4CompletedSupportive CareAdult Refractory Complex Partial Seizures1
4RecruitingTreatmentEpilepsies1
4TerminatedTreatmentComplex Partial Seizures1
4WithdrawnNot AvailableInfantile Spasms (IS)1
Not AvailableCompletedNot AvailableInfantile Spasms (IS) / Refractory Complex Partial Seizures in Adults1
Not AvailableRecruitingTreatmentAutoimmune encephalopathy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Lundbeck Inc.
Dosage forms
FormRouteStrength
PowderOral500 mg
TabletOral500 mg
Tablet, film coatedOral500 mg/1
PowderOral1 g
PowderOral2 g
PowderOral3 g
For solutionOral500 mg/1
Powder, for solutionOral50 mg/1mL
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.
Patents
Not Available

Properties

State
Solid
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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 inhibitorNon-inhibitor0.9389
CYP450 2D6 inhibitorNon-inhibitor0.9654
CYP450 2C19 inhibitorNon-inhibitor0.963
CYP450 3A4 inhibitorNon-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
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
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9400000000-0215823a9ba364cc48cb
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9400000000-c7d21d36dfb8e7079ee2
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9200000000-e0c504f980ef5bbc0501
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9000000000-e1b2ea8d5a2da84a5a64
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9000000000-52958176067fd9bae916
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9000000000-263da4b132ca66986967
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-01b9-9000000000-1f8826cc32ef269c1a7c
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-014i-9000000000-32306e2f90cd529accc7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0gb9-9000000000-aefa9f2682087c7b78ed

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Gamma amino acids and derivatives
Alternative Parents
Medium-chain fatty acids / Amino fatty acids / Unsaturated fatty acids / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives
show 1 more
Substituents
Gamma amino acid or derivatives / Medium-chain fatty acid / Amino fatty acid / Unsaturated fatty acid / Fatty acyl / Fatty acid / Amino acid / Carboxylic acid / Monocarboxylic acid or derivatives / Amine
show 11 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
gamma-amino acid (CHEBI:63638)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled gaba receptor activity
Specific Function
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coup...
Gene Name
GABBR1
Uniprot ID
Q9UBS5
Uniprot Name
Gamma-aminobutyric acid type B receptor subunit 1
Molecular Weight
108319.4 Da
References
  1. Tyacke RJ, Lingford-Hughes A, Reed LJ, Nutt DJ: GABAB receptors in addiction and its treatment. Adv Pharmacol. 2010;58:373-96. doi: 10.1016/S1054-3589(10)58014-1. [PubMed:20655489]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Succinate-semialdehyde dehydrogenase binding
Specific Function
Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. Can also convert delta-aminovalerate and beta-al...
Gene Name
ABAT
Uniprot ID
P80404
Uniprot Name
4-aminobutyrate aminotransferase, mitochondrial
Molecular Weight
56438.405 Da
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:10195585]
  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:10206175]
  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:10214744]
  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:10503933]
  5. French JA: Vigabatrin. Epilepsia. 1999;40 Suppl 5:S11-6. [PubMed:10530689]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Vigabitrin [Link]
  2. FDA approved label, Vigabatrin [File]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
L-proline transmembrane transporter activity
Specific Function
Neutral amino acid/proton symporter. Has a pH-dependent electrogenic transport activity for small amino acids such as glycine, alanine and proline. Besides small apolar L-amino acids, it also recog...
Gene Name
SLC36A1
Uniprot ID
Q7Z2H8
Uniprot Name
Proton-coupled amino acid transporter 1
Molecular Weight
53075.045 Da
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:16331283]

Drug created on June 13, 2005 07:24 / Updated on November 14, 2018 12:49