DT-Web

DB00230 - Pregabalin


Identification
Name Pregabalin
Accession Number DB00230 (APRD01198)
Type small molecule
Description Pregabalin is an anticonvulsant drug used for neuropathic pain, as an adjunct therapy for partial seizures, and in generalized anxiety disorder. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade name Lyrica. It is considered to have a dependence liability if misused, and is classified as a Schedule V drug in the U.S. [Wikipedia]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 159.2261
Groups illicit
Monoisotopic Weight 159.125928793
Pharmacology
Indication Pregabalin is used for the management of neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, and postherpetic neuralgia. It is also used as adjunctive therapy for adult patients with partial onset seizures and management of fibromyalgia.
Mechanism of action Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's antinociceptive and antiseizure effects in animal models. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of calcium channel function. Studies also suggest that the descending noradrenergic and serotonergic pathways originating from the brainstem may be involved with the mechanism of pregabalin. Interestingly, although pregabalin is a structural derivative of inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or benzodiazepine receptors. The sodium channels, opiate receptors, and cyclooxygenase enzymes are not involved with the mechanism of pregabalin. It is also inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
Absorption Pregabalin is well absorbed after oral administration. When an oral administration of pregabalin under fasting conditions is given, the pharmacokinetic parameters are as follows: Tmax = 1.5 hours; Oral bioavailability = >90% (independent of dose); Time to steady state = 24-48 hours. It is also a substrate for the L-type transport system.
Protein binding Pregabalin does not bind to plasma proteins.
Biotransformation Pregabalin undergoes negligible metabolism in humans.
Route of elimination 90% of the dose was recovered in the urine as the parent compound. The N-methylated derivative of pregabalin, the major metabolite was found in the urine and accounted for 0.9% of the dose. Pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer.
Toxicity Most common adverse reactions (>=5% and twice placebo) are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention).
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Triprolidine The CNS depressants, Triprolidine and Pregabalin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food Interactions
  • Avoid alcohol (may increase CNS effects).
  • When taken with food, Cmax decreases, while Tmax is prolonged. Despite these observations, the total absorption of pregabalin is not effected to a clinically relevant degree. Pregabalin can be taken with or without food.

Targets


Voltage-dependent P/Q-type calcium channel subunit alpha-1A
Name Voltage-dependent P/Q-type calcium channel subunit alpha-1A
Gene Name CACNA1A
Pharmacological action yes
Actions inhibitor
References
  • Gazulla J, Tintore M: The P/Q-type voltage-dependent calcium channel: a therapeutic target in spinocerebellar ataxia type 6. Acta Neurol Scand. 2007 May;115(5):356-63. - Pubmed
  • Gazulla J, Tintore MA: The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit. Med Hypotheses. 2007;68(1):131-6. Epub 2006 Aug 8. - Pubmed
  • Jacquy J, Lossignol D, Sternon J: [Pregabalin (Lyrica) and neuropathic pain syndromes] Rev Med Brux. 2006 Sep-Oct;27(5):445-50. - Pubmed
  • Taylor CP, Angelotti T, Fauman E: Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007 Feb;73(2):137-50. Epub 2006 Nov 28. - Pubmed
  • Field MJ, Cox PJ, Stott E, Melrose H, Offord J, Su TZ, Bramwell S, Corradini L, England S, Winks J, Kinloch RA, Hendrich J, Dolphin AC, Webb T, Williams D: Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17537-42. Epub 2006 Nov 6. - Pubmed
DTHybrid score 0.446

Transporters


Excitatory amino acid transporter 3
Name Excitatory amino acid transporter 3
Gene Name SLC1A1
Actions Other
References
  • Ryu JH, Lee PB, Kim JH, Do SH, Kim CS: Effects of pregabalin on the activity of glutamate transporter type 3. Br J Anaesth. 2012 Aug;109(2):234-9. doi: 10.1093/bja/aes120. Epub 2012 Apr 16. - Pubmed
DTHybrid score 0.4622

Predictions


Id Partner name Gene Name Score
465 Calmodulin CALM1 0.0351
741 Potassium voltage-gated channel subfamily KQT member 1 KCNQ1 0.03
1262 Corticotropin-lipotropin POMC 0.0274
6047 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A PDE1A 0.027
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0251
2632 Adenylosuccinate synthetase purA 0.0243
3323 Adenylosuccinate synthetase purA 0.0243
3975 Adenylosuccinate synthetase ADSS 0.0243
4598 Adenylosuccinate synthetase Adss 0.0243
6817 Adenylosuccinate synthetase purA 0.0243
209 Aspartoacylase ASPA 0.0242
3979 Aspartoacylase-2 ACY3 0.0242
799 Aspartyl-tRNA synthetase, cytoplasmic DARS 0.0242
533 Aminoacylase-1 ACY1 0.0242
262 Calcium-binding mitochondrial carrier protein Aralar1 SLC25A12 0.0242
3969 Multifunctional protein ADE2 [Includes: Phosphoribosylaminoimidazole- succinocarboxamide synthase PAICS 0.0242
3972 Adenylosuccinate synthetase isozyme 2 ADSS 0.0242
3976 Aspartyl-tRNA synthetase, mitochondrial DARS2 0.0242
513 Calcium-binding mitochondrial carrier protein Aralar2 SLC25A13 0.0242
305 Mitochondrial aspartate-glutamate carrier protein SLC25A13 0.0242
3877 Growth-inhibiting protein 18 GIG18 0.0236
1588 Multidrug resistance protein 1 ABCB1 0.0236
4119 Cytochrome P450 2D6 CYP2D6 0.0235
4160 Voltage-dependent calcium channel subunit alpha-2/delta-2 CACNA2D2 0.0231
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.023
426 Aspartate aminotransferase, mitochondrial GOT2 0.0215
242 Asparagine synthetase [glutamine-hydrolyzing] ASNS 0.0214
586 Aspartate aminotransferase, cytoplasmic GOT1 0.0209
585 Aspartyl/asparaginyl beta-hydroxylase ASPH 0.0207
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0205
3977 ASRGL1 protein ASRGL1 0.0201
806 Sodium/potassium-transporting ATPase alpha-1 chain ATP1A1 0.0192
3971 CAD protein [Includes: Glutamine-dependent carbamoyl-phosphate synthase CAD 0.0181
467 Delta-type opioid receptor OPRD1 0.0167
696 Kappa-type opioid receptor OPRK1 0.0165
740 Argininosuccinate synthase ASS1 0.0162
865 Argininosuccinate synthase ASS1 0.0162
2680 Argininosuccinate synthase argG 0.0162
3194 Argininosuccinate synthase argG 0.0162
6030 Cytochrome P450 2B6 CYP2B6 0.0159
847 Mu-type opioid receptor OPRM1 0.0158
4924 Cytochrome P450 2C8 CYP2C8 0.0146
6151 Monocarboxylate transporter 10 SLC16A10 0.0143
3978 Adenylosuccinate synthetase isozyme 1 ADSSL1 0.0129
4512 Cytochrome P450 3A4 CYP3A4 0.0118
5682 Ribonuclease pancreatic RNASE1 0.0096
1912 Excitatory amino acid transporter 1 SLC1A3 0.0085
4016 Excitatory amino acid transporter 5 SLC1A7 0.0085
4019 Excitatory amino acid transporter 4 SLC1A6 0.0084
1047 Excitatory amino acid transporter 2 SLC1A2 0.0084
4026 Aspartyl aminopeptidase DNPEP 0.0083
4024 Mitochondrial glutamate carrier 2 SLC25A18 0.0083
4023 N-acetylglutamate synthase, mitochondrial NAGS 0.0083
915 Delta 1-pyrroline-5-carboxylate synthetase ALDH18A1 0.0083
4022 Glutamate--ammonia ligase domain-containing protein 1 LGSN 0.0083
4021 Probable glutamyl-tRNA synthetase, mitochondrial EARS2 0.0083
4025 Mitochondrial glutamate carrier 1 SLC25A22 0.0083
664 Glutamate decarboxylase 2 GAD2 0.0083
3890 Glutamate decarboxylase 2 GAD2 0.0083
4020 Glutamyl aminopeptidase ENPEP 0.0083
920 Glutamate receptor, ionotropic kainate 5 GRIK5 0.0083
4027 Glutamate receptor delta-1 subunit GRID1 0.0083
922 Glutamate receptor 4 GRIA4 0.0083
927 Metabotropic glutamate receptor 8 GRM8 0.0083
925 Metabotropic glutamate receptor 4 GRM4 0.0083
926 Metabotropic glutamate receptor 7 GRM7 0.0083
924 Glutamate receptor, ionotropic kainate 3 GRIK3 0.0083
919 Glutamate receptor, ionotropic kainate 4 GRIK4 0.0083
4018 Glutamate receptor delta-2 subunit GRID2 0.0083
4017 5-oxoprolinase OPLAH 0.0083
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0072
4114 Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 0.0071
4112 Voltage-dependent L-type calcium channel subunit beta-4 CACNB4 0.0071
668 Glutamate--cysteine ligase regulatory subunit GCLM 0.007
5 Glutaminase liver isoform, mitochondrial GLS2 0.0069
917 Glutaminase kidney isoform, mitochondrial GLS 0.0069
355 GMP synthase [glutamine-hydrolyzing] GMPS 0.0069
4353 GMP synthase [glutamine-hydrolyzing] guaA 0.0069
3991 Glutamine-dependent NAD(+) synthetase NADSYN1 0.0069
3984 Probable glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial PET112L 0.0069
3982 Phosphoribosylformylglycinamidine synthase PFAS 0.0069
5261 Phosphoribosylformylglycinamidine synthase purL 0.0069
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0065
333 Voltage-dependent L-type calcium channel subunit beta-1 CACNB1 0.0065
830 Glutamate dehydrogenase 2, mitochondrial GLUD2 0.0064
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0064
781 ATP-sensitive inward rectifier potassium channel 11 KCNJ11 0.0063
801 Kynurenine/alpha-aminoadipate aminotransferase mitochondrial AADAT 0.0061
3895 Kynurenine--oxoglutarate transaminase 3 CCBL2 0.0061
665 Phosphoserine aminotransferase PSAT1 0.0061
4652 Phosphoserine aminotransferase serC 0.0061
420 Glutamate decarboxylase 1 GAD1 0.0061
3900 Glutamate decarboxylase 1 GAD1 0.0061
382 Glutamate receptor, ionotropic kainate 1 GRIK1 0.0061
625 Glutamate carboxypeptidase 2 FOLH1 0.006
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.006
186 Glutamate--cysteine ligase catalytic subunit GCLC 0.0059
916 Metabotropic glutamate receptor 1 GRM1 0.0057
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0054
448 Vitamin K-dependent gamma-carboxylase GGCX 0.0054
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0054
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0054
923 Glutamate receptor 3 GRIA3 0.0053
201 Glutamate dehydrogenase 1, mitochondrial GLUD1 0.0053
763 Tyrosine aminotransferase TAT 0.0053
5493 Tyrosine aminotransferase Not Available 0.0053
735 Alanine aminotransferase 1 GPT 0.0053
3904 Alanine aminotransferase 2 GPT2 0.0053
773 Folylpolyglutamate synthase, mitochondrial FPGS 0.0053
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0053
6148 Multidrug resistance-associated protein 7 ABCC10 0.0052
914 Formimidoyltransferase-cyclodeaminase FTCD 0.0052
505 Glutamate [NMDA] receptor subunit epsilon-3 GRIN2C 0.0051
83 Alpha-aminoadipic semialdehyde synthase, mitochondrial AASS 0.0051
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.005
210 Bifunctional aminoacyl-tRNA synthetase [Includes: Glutamyl-tRNA synthetase EPRS 0.0049
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.0049
574 Branched-chain-amino-acid aminotransferase, cytosolic BCAT1 0.0049
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.0048
6106 Cytochrome P450 2C18 CYP2C18 0.0048
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0047
833 Organic cation/carnitine transporter 1 SLC22A4 0.0047
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0047
795 Branched-chain-amino-acid aminotransferase, mitochondrial BCAT2 0.0047
705 Glutamate receptor 1 GRIA1 0.0046
280 4-aminobutyrate aminotransferase, mitochondrial ABAT 0.0046
3426 Glutamine synthetase glnA 0.0045
3987 Glutamine synthetase GLUL 0.0045
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.0044
33 Cystine/glutamate transporter SLC7A11 0.0044
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0044
776 Bile salt export pump ABCB11 0.0044
824 Sodium-dependent serotonin transporter SLC6A4 0.0043
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0043
2164 Multidrug resistance-associated protein 4 ABCC4 0.0043
118 Organic cation/carnitine transporter 2 SLC22A5 0.0041
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.004
862 Multidrug resistance-associated protein 1 ABCC1 0.004
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.004
6145 Solute carrier family 22 member 1 SLC22A1 0.0039
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0038
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0037
738 Monocarboxylate transporter 1 SLC16A1 0.0036
6107 Cytochrome P450 3A7 CYP3A7 0.0035
918 Glutamate receptor, ionotropic kainate 2 GRIK2 0.0034
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0034
4118 Cytochrome P450 3A5 CYP3A5 0.0033
6016 Cytochrome P450 2C19 CYP2C19 0.0031
4200 Cytochrome P450 1A2 CYP1A2 0.0031
921 Glutamate receptor 2 GRIA2 0.0031
4757 Cytochrome P450 2C9 CYP2C9 0.003
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