DT-Web

DB01080 - Vigabatrin


Identification
Name Vigabatrin
Accession Number DB01080 (APRD00282)
Type small molecule
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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 129.157
Groups approved
Monoisotopic Weight 129.078978601
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.
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.
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.
Protein binding Not protein bound
Biotransformation Almost no metabolic transformation. Does not induce the hepatic cytochrome P450 system.
Route of elimination Eliminated primarily through renal excretion as unchanged drugs (80%).
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
Interactions
Drug Interactions
Drug Mechanism of interaction
Clonazepam Vigabatrin increases Cmax of clonazepam by 30% and decreases Tmax by 45%
Fosphenytoin Vigabatrin decreases the effect of hydantoin
Mefloquine Mefloquine 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.
Methotrimeprazine Additive 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.
Phenobarbital Vigabatrin reduces serum concentrations of phenobarbital by 8-16%.
Phenytoin Vigabatrin reduces plasma levels of phenytoin by 16-20% which may be due to induction of CYP2C. Consider dosage adjustment.
Sildenafil Increased anticonvulsant effects of vigabatrin due to pharmacodynamic synergism. Monitor for adverse effects during concomitant therapy.
Triprolidine The CNS depressants, Triprolidine and Vigabatrin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Valproic Acid Vigabatrin reduces serum concentrations of valproic acid by 8%.
Food Interactions Not Available

Targets


Gamma-aminobutyric acid type B receptor, subunit 1
Name Gamma-aminobutyric acid type B receptor, subunit 1
Gene Name GABBR1
Pharmacological action yes
Actions agonist
References
  • Tyacke RJ, Lingford-Hughes A, Reed LJ, Nutt DJ: GABAB receptors in addiction and its treatment. Adv Pharmacol. 2010;58:373-96. - Pubmed
DTHybrid score 0.755
4-aminobutyrate aminotransferase, mitochondrial
Name 4-aminobutyrate aminotransferase, mitochondrial
Gene Name ABAT
Pharmacological action yes
Actions inhibitor
References
  • 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
  • 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
  • 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
  • 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
  • French JA: Vigabatrin. Epilepsia. 1999;40 Suppl 5:S11-6. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.6128

Transporters


Proton-coupled amino acid transporter 1
Name Proton-coupled amino acid transporter 1
Gene Name SLC36A1
Actions Not Available
References
  • 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
DTHybrid score 1.0091

Predictions


Id Partner name Gene Name Score
4094 Gamma-aminobutyric acid type B receptor, subunit 2 GABBR2 0.1899
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0971
6142 Solute carrier family 22 member 8 SLC22A8 0.0663
114 Alanine--glyoxylate aminotransferase 2, mitochondrial AGXT2 0.0421
4096 Metabotropic glutamate receptor 3 GRM3 0.0401
1362 Metabotropic glutamate receptor 2 GRM2 0.04
735 Alanine aminotransferase 1 GPT 0.0399
3904 Alanine aminotransferase 2 GPT2 0.0399
916 Metabotropic glutamate receptor 1 GRM1 0.0382
2178 Metabotropic glutamate receptor 5 GRM5 0.0375
532 Neutral amino acid transporter A SLC1A4 0.0359
4070 Probable alanyl-tRNA synthetase, mitochondrial AARS2 0.0359
323 Alanyl-tRNA synthetase, cytoplasmic AARS 0.0359
349 Serine--pyruvate aminotransferase AGXT 0.0309
3899 Alanine--glyoxylate aminotransferase 2-like 2 AGXT2L2 0.0306
435 Kynureninase KYNU 0.0293
4654 Kynureninase kynU 0.0293
169 Cysteine desulfurase, mitochondrial NFS1 0.0289
6151 Monocarboxylate transporter 10 SLC16A10 0.0288
866 Large neutral amino acids transporter small subunit 2 SLC7A8 0.0249
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0222
3913 Glutamic acid decarboxylase GAD65 0.0142
218 Monocarboxylate transporter 5 SLC16A4 0.0126
738 Monocarboxylate transporter 1 SLC16A1 0.0126
397 Monocarboxylate transporter 3 SLC16A8 0.0126
429 Monocarboxylate transporter 6 SLC16A5 0.0126
195 Monocarboxylate transporter 7 SLC16A6 0.0126
1483 Membrane copper amine oxidase AOC3 0.0112
52 Pyruvate kinase isozymes R/L PKLR 0.0104
110 Pyruvate dehydrogenase E1 component subunit beta, mitochondrial PDHB 0.0102
771 Pyruvate carboxylase, mitochondrial PC 0.0101
98 Pyruvate kinase isozymes M1/M2 PKM2 0.0091
199 Monocarboxylate transporter 8 SLC16A2 0.0087
575 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial GCAT 0.0085
455 5-aminolevulinate synthase, nonspecific, mitochondrial ALAS1 0.0085
681 Glycine dehydrogenase [decarboxylating], mitochondrial GLDC 0.0085
500 Monocarboxylate transporter 4 SLC16A3 0.0084
489 Monocarboxylate transporter 2 SLC16A7 0.0083
1039 Histone deacetylase 9 HDAC9 0.008
6031 Cytochrome P450 3A43 CYP3A43 0.008
4058 Glycine N-acyltransferase-like protein 2 GLYATL2 0.0079
4056 N-arachidonyl glycine receptor GPR18 0.0079
4061 Peroxisomal sarcosine oxidase PIPOX 0.0079
4055 Bile acid CoA:amino acid N-acyltransferase BAAT 0.0079
1236 Sodium- and chloride-dependent glycine transporter 1 SLC6A9 0.0079
4060 Vesicular inhibitory amino acid transporter SLC32A1 0.0079
4057 Glycine N-acyltransferase GLYAT 0.0079
4059 Glycine N-acyltransferase-like protein 1 GLYATL1 0.0079
1088 5-aminolevulinate synthase, erythroid-specific, mitochondrial ALAS2 0.0079
1466 Glycyl-tRNA synthetase GARS 0.0079
4062 Sodium- and chloride-dependent glycine transporter 2 SLC6A5 0.0079
3884 SHMT2 protein SHMT2 0.0077
3901 SHMT2 protein SHMT2 0.0077
3885 Hypothetical protein DKFZp686P09201 DKFZp686P09201 0.0077
3879 Serine hydroxymethyltransferase 2 Not Available 0.0077
321 Serine hydroxymethyltransferase, mitochondrial SHMT2 0.0077
6152 Solute carrier organic anion transporter family member 2A1 SLCO2A1 0.0074
505 Glutamate [NMDA] receptor subunit epsilon-3 GRIN2C 0.0074
4118 Cytochrome P450 3A5 CYP3A5 0.0073
4924 Cytochrome P450 2C8 CYP2C8 0.0072
630 Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial ACADSB 0.007
367 Serine hydroxymethyltransferase, cytosolic SHMT1 0.0069
6016 Cytochrome P450 2C19 CYP2C19 0.0069
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.0069
3939 Amine oxidase [flavin-containing] B MAOB 0.0067
3941 Amine oxidase [flavin-containing] A MAOA 0.0066
4054 Glycine cleavage system H protein, mitochondrial GCSH 0.0066
182 2-oxoglutarate dehydrogenase E1 component, mitochondrial OGDH 0.0064
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0063
62 Glycine receptor subunit beta GLRB 0.0061
383 Glycine amidinotransferase, mitochondrial GATM 0.006
411 Glycine N-methyltransferase GNMT 0.0059
4512 Cytochrome P450 3A4 CYP3A4 0.0058
207 Glutathione synthetase GSS 0.0057
5269 Glutathione synthetase gshB 0.0057
170 Succinate semialdehyde dehydrogenase, mitochondrial ALDH5A1 0.0056
6177 UDP-glucuronosyltransferase 1-10 UGT1A10 0.005
6013 Cytochrome P450 2E1 CYP2E1 0.005
6181 UDP-glucuronosyltransferase 1-8 UGT1A8 0.005
665 Phosphoserine aminotransferase PSAT1 0.005
4652 Phosphoserine aminotransferase serC 0.005
420 Glutamate decarboxylase 1 GAD1 0.005
3900 Glutamate decarboxylase 1 GAD1 0.005
801 Kynurenine/alpha-aminoadipate aminotransferase mitochondrial AADAT 0.005
3895 Kynurenine--oxoglutarate transaminase 3 CCBL2 0.005
461 Glycine receptor subunit alpha-3 GLRA3 0.005
6107 Cytochrome P450 3A7 CYP3A7 0.005
820 Glycine receptor subunit alpha-2 GLRA2 0.0049
3877 Growth-inhibiting protein 18 GIG18 0.0046
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0045
426 Aspartate aminotransferase, mitochondrial GOT2 0.0044
763 Tyrosine aminotransferase TAT 0.0044
5493 Tyrosine aminotransferase Not Available 0.0044
914 Formimidoyltransferase-cyclodeaminase FTCD 0.0043
482 Glycine receptor subunit alpha-1 GLRA1 0.0042
586 Aspartate aminotransferase, cytoplasmic GOT1 0.0042
795 Branched-chain-amino-acid aminotransferase, mitochondrial BCAT2 0.004
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0039
574 Branched-chain-amino-acid aminotransferase, cytosolic BCAT1 0.0039
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0038
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0037
6106 Cytochrome P450 2C18 CYP2C18 0.0037
6143 Solute carrier family 22 member 7 SLC22A7 0.0034
118 Organic cation/carnitine transporter 2 SLC22A5 0.0033
4026 Aspartyl aminopeptidase DNPEP 0.0031
4024 Mitochondrial glutamate carrier 2 SLC25A18 0.0031
4025 Mitochondrial glutamate carrier 1 SLC25A22 0.0031
915 Delta 1-pyrroline-5-carboxylate synthetase ALDH18A1 0.0031
4019 Excitatory amino acid transporter 4 SLC1A6 0.0031
1047 Excitatory amino acid transporter 2 SLC1A2 0.0031
919 Glutamate receptor, ionotropic kainate 4 GRIK4 0.0031
4022 Glutamate--ammonia ligase domain-containing protein 1 LGSN 0.0031
4021 Probable glutamyl-tRNA synthetase, mitochondrial EARS2 0.0031
4023 N-acetylglutamate synthase, mitochondrial NAGS 0.0031
1912 Excitatory amino acid transporter 1 SLC1A3 0.0031
4016 Excitatory amino acid transporter 5 SLC1A7 0.0031
664 Glutamate decarboxylase 2 GAD2 0.0031
3890 Glutamate decarboxylase 2 GAD2 0.0031
922 Glutamate receptor 4 GRIA4 0.0031
927 Metabotropic glutamate receptor 8 GRM8 0.0031
925 Metabotropic glutamate receptor 4 GRM4 0.0031
926 Metabotropic glutamate receptor 7 GRM7 0.0031
924 Glutamate receptor, ionotropic kainate 3 GRIK3 0.0031
4020 Glutamyl aminopeptidase ENPEP 0.0031
920 Glutamate receptor, ionotropic kainate 5 GRIK5 0.0031
4018 Glutamate receptor delta-2 subunit GRID2 0.0031
4027 Glutamate receptor delta-1 subunit GRID1 0.0031
4017 5-oxoprolinase OPLAH 0.0031
5718 Cytochrome P450 2A6 CYP2A6 0.003
20 Prostaglandin G/H synthase 1 PTGS1 0.003
1729 Solute carrier family 22 member 6 SLC22A6 0.0028
6030 Cytochrome P450 2B6 CYP2B6 0.0027
668 Glutamate--cysteine ligase regulatory subunit GCLM 0.0027
3883 Ornithine aminotransferase variant Not Available 0.0026
3896 CDNA FLJ46802 fis, clone TRACH3032150, moderately similar to Cysteine sulfinic acid decarboxylase GADL1 0.0026
3911 Uncharacterized protein C20orf38 SPTLC3 0.0026
3881 Selenocysteine lyase variant Not Available 0.0026
3887 Phosphorylase PYGB 0.0026
3915 Cysteine sulfinic acid decarboxylase-related protein 1 CSAD 0.0026
3914 Alanine-glyoxylate aminotransferase homolog TLH6 0.0026
3878 GAD1 protein GAD1 0.0026
306 Pyridoxal phosphate phosphatase PDXP 0.0026
3906 Serine dehydratase-like SDSL 0.0026
3891 Putative L-Dopa decarboxylase DDC 0.0026
3903 Aminolevulinate, delta-, synthase 2 ALAS2 0.0026
3880 Serine hydroxymethyltransferase 1 Not Available 0.0026
3908 P-selectin cytoplasmic tail-associated protein pcap 0.0026
3893 DDC protein DDC 0.0026
3910 O-phosphoseryl-tRNA(Sec) selenium transferase SEPSECS 0.0026
855 Sphingosine-1-phosphate lyase 1 SGPL1 0.0026
3886 Migration-inducing protein 4 ALAS1 0.0026
3909 Hepatic peroxysomal alanine:glyoxylate aminotransferase Not Available 0.0026
3894 KIAA0251 protein PDXDC1 0.0026
3875 Glycogen phosphorylase, brain form PYGB 0.0026
3882 Brain glycogen phosphorylase variant Not Available 0.0026
3905 Molybdenum cofactor sulfurase MOCOS 0.0026
3984 Probable glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial PET112L 0.0026
5 Glutaminase liver isoform, mitochondrial GLS2 0.0026
917 Glutaminase kidney isoform, mitochondrial GLS 0.0026
355 GMP synthase [glutamine-hydrolyzing] GMPS 0.0026
4353 GMP synthase [glutamine-hydrolyzing] guaA 0.0026
3991 Glutamine-dependent NAD(+) synthetase NADSYN1 0.0026
3982 Phosphoribosylformylglycinamidine synthase PFAS 0.0026
5261 Phosphoribosylformylglycinamidine synthase purL 0.0026
830 Glutamate dehydrogenase 2, mitochondrial GLUD2 0.0026
625 Glutamate carboxypeptidase 2 FOLH1 0.0025
727 Serine palmitoyltransferase 2 SPTLC2 0.0024
491 Serine palmitoyltransferase 1 SPTLC1 0.0024
89 Cysteine sulfinic acid decarboxylase CSAD 0.0024
184 L-serine dehydratase SDS 0.0024
431 Serine racemase SRR 0.0024
3874 Proline synthetase co-transcribed bacterial homolog protein PROSC 0.0024
382 Glutamate receptor, ionotropic kainate 1 GRIK1 0.0024
534 Threonine synthase-like 1 THNSL1 0.0024
4200 Cytochrome P450 1A2 CYP1A2 0.0024
3 Histidine decarboxylase HDC 0.0024
1671 Excitatory amino acid transporter 3 SLC1A1 0.0024
499 Arginine decarboxylase ADC 0.0024
186 Glutamate--cysteine ligase catalytic subunit GCLC 0.0023
4757 Cytochrome P450 2C9 CYP2C9 0.0023
923 Glutamate receptor 3 GRIA3 0.0023
448 Vitamin K-dependent gamma-carboxylase GGCX 0.0022
201 Glutamate dehydrogenase 1, mitochondrial GLUD1 0.0022
472 Ornithine aminotransferase, mitochondrial OAT 0.0022
358 Cystathionine beta-synthase CBS 0.0022
773 Folylpolyglutamate synthase, mitochondrial FPGS 0.0022
83 Alpha-aminoadipic semialdehyde synthase, mitochondrial AASS 0.0022
203 Pyridoxine-5'-phosphate oxidase PNPO 0.0021
210 Bifunctional aminoacyl-tRNA synthetase [Includes: Glutamyl-tRNA synthetase EPRS 0.0021
868 Cystathionine gamma-lyase CTH 0.0021
242 Asparagine synthetase [glutamine-hydrolyzing] ASNS 0.0021
301 Kynurenine--oxoglutarate transaminase 1 CCBL1 0.0021
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.002
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.0019
449 Ornithine decarboxylase ODC1 0.0019
705 Glutamate receptor 1 GRIA1 0.0019
33 Cystine/glutamate transporter SLC7A11 0.0019
3426 Glutamine synthetase glnA 0.0019
3987 Glutamine synthetase GLUL 0.0019
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0018
3876 Aromatic-L-amino-acid decarboxylase DDC 0.0018
10 Glycogen phosphorylase, liver form PYGL 0.0017
918 Glutamate receptor, ionotropic kainate 2 GRIK2 0.0014
921 Glutamate receptor 2 GRIA2 0.0013
1152 Glycogen phosphorylase, muscle form PYGM 0.0013
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