DT-Web

DB04953 - Ezogabine


Identification
Name Ezogabine
Accession Number DB04953
Type small molecule
Description Ezogabine (D23129) is a close structural analog of the centrally acting analgesic flupitrine. It is a neuronal potassium channel opener being developed as a first-in-class antiepileptic drug (AED) and is currently being studied in Phase 3 trials as an adjunctive treatment for partial-onset seizures in adult patients with refractory epilepsy. FDA approved in June 10, 2011 under the name of ezogabine.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 303.3314
Groups approved
Monoisotopic Weight 303.13830504
Pharmacology
Indication Adjuvant treatment of partial-onset seizures.
Mechanism of action Ezogabine has a novel mechanism of action that involves opening of neuronal Kv7.2-7.5 (formerly KCNQ2-5) voltage activated potassium channels. These channels (primarily Kv7.2/7.3) enable generation of the M-current, a sub-threshold potassium current that serves to stabilize the membrane potential and control neuronal excitability. In addition to acting on potassium ion channels, retigabine also affects GABA neurotransmission in the GABA-A receptor, which is a key inhibitory receptor in the central nervous system and is implicated in epilepsy. Malfunctioning of the GABA-A receptor leads to hyperexcitability in the brain, which causes seizures, making this receptor an important target for antiepileptic therapeutics. Apart from increasing the concentration of GABA in the brain (by either enhancing GABA synthesis or blocking GABA metabolism), retigabine allosterically potentiates GABA-induced current in rat cortical neurons in a concentration-dependent manner. Numerous studies have demonstrated that retigabine is effective in a broad spectrum of in vivo epilepsy and seizure models.
Absorption Rapidly absorbed and distributed, with an absolute oral bioavailability of 60%. Pharmacokinetics of ezogabine suggest first-order kinetics. Tmax, single oral dose = 30-120 minutes; Time to steady state = 3 days
Protein binding Approximately 80% protein bound.
Biotransformation Ezogabine is metabolized exclusively via phase II hepatic N-glucurodination and acetylation. N-glucurodination is the major metabolic pathway of the two and form two major N-glucuronide metabolites. The enzymes involved are UGT1A1, 1A9, 1A4, and 1A3. However, the product of the N-acetyl pathway is a weak, active metabolite referred to as NAMR. The enzyme that is involved in the N-acetyl pathway is called N-acetyltransferase 2. The pharmacokinetics of NAMR and ezogabine are similar. The cytochrome P450 enzyme system is not involved with the metabolism of ezogabine.
Route of elimination Urine (85%, 36% of total dose as unchanged drug, 18% of total dose as NAMR) and feces (14%, 3% of total dose as unchanged drug)
Toxicity Lethal Dose, acute, oral, rat = 100 mg/kg; Lethal Dose, chronic, oral, rat = 5.1 mg/kg/day, 90-day; Most common adverse effects that lead to discontinuation of therapy include dizziness and somnolence.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Carbamazepine Ezogabine increases the clearance of carbamazepine (30%). The mechanism of this interaction is unknown.
Lamotrigine In healthy adults, the AUCs of lamotrigine and ezogabine were both increased. The clinical significance of this is still unknown. Multiple doses of ezogabine also increase the clearance and decrease the terminal half-life of lamotrigine.
Ondansetron Concurrent use of ezogabine and ondansetron can increase QTc interval. Consider alternate therapy.
Phenytoin Ezogabine increases the clearance of phenytoin (30%). The mechanism of this interaction is unknown.
Food Interactions
  • With a high-fat meal, Cmax is moderately increased.

Targets


Potassium voltage-gated channel subfamily KQT member 2
Name Potassium voltage-gated channel subfamily KQT member 2
Gene Name KCNQ2
Pharmacological action unknown
Actions Not Available
References
  • Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H: The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol. 2005 Apr;67(4):1009-17. Epub 2005 Jan 20. - Pubmed
  • Hirano K, Kuratani K, Fujiyoshi M, Tashiro N, Hayashi E, Kinoshita M: Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice. Neurosci Lett. 2007 Feb 14;413(2):159-62. Epub 2006 Dec 20. - Pubmed
  • Punke MA, Friederich P: Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels. Anesth Analg. 2007 May;104(5):1256-64, tables of contents. - Pubmed
  • Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA: Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol. 2000 Aug;58(2):253-62. - Pubmed
  • Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK: Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol. 2000 Sep;58(3):591-600. - Pubmed
DTHybrid score 0.5011
Potassium voltage-gated channel subfamily KQT member 3
Name Potassium voltage-gated channel subfamily KQT member 3
Gene Name KCNQ3
Pharmacological action unknown
Actions Not Available
References
  • Hirano K, Kuratani K, Fujiyoshi M, Tashiro N, Hayashi E, Kinoshita M: Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice. Neurosci Lett. 2007 Feb 14;413(2):159-62. Epub 2006 Dec 20. - Pubmed
  • Punke MA, Friederich P: Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels. Anesth Analg. 2007 May;104(5):1256-64, tables of contents. - Pubmed
  • Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA: Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol. 2000 Aug;58(2):253-62. - Pubmed
  • Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK: Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol. 2000 Sep;58(3):591-600. - Pubmed
DTHybrid score 0.5369
Potassium voltage-gated channel subfamily KQT member 4
Name Potassium voltage-gated channel subfamily KQT member 4
Gene Name KCNQ4
Pharmacological action unknown
Actions Not Available
References
  • Hirano K, Kuratani K, Fujiyoshi M, Tashiro N, Hayashi E, Kinoshita M: Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice. Neurosci Lett. 2007 Feb 14;413(2):159-62. Epub 2006 Dec 20. - Pubmed
  • Schroder RL, Jespersen T, Christophersen P, Strobaek D, Jensen BS, Olesen SP: KCNQ4 channel activation by BMS-204352 and retigabine. Neuropharmacology. 2001 Jun;40(7):888-98. - Pubmed
  • Borlak J, Gasparic A, Locher M, Schupke H, Hermann R: N-Glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Metabolism. 2006 Jun;55(6):711-21. - Pubmed
DTHybrid score 0.5543
Potassium voltage-gated channel subfamily KQT member 5
Name Potassium voltage-gated channel subfamily KQT member 5
Gene Name KCNQ5
Pharmacological action unknown
Actions Not Available
References
  • Hirano K, Kuratani K, Fujiyoshi M, Tashiro N, Hayashi E, Kinoshita M: Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice. Neurosci Lett. 2007 Feb 14;413(2):159-62. Epub 2006 Dec 20. - Pubmed
  • Hermann R, Ferron GM, Erb K, Knebel N, Ruus P, Paul J, Richards L, Cnota HP, Troy S: Effects of age and sex on the disposition of retigabine. Clin Pharmacol Ther. 2003 Jan;73(1):61-70. - Pubmed
  • Borlak J, Gasparic A, Locher M, Schupke H, Hermann R: N-Glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Metabolism. 2006 Jun;55(6):711-21. - Pubmed
DTHybrid score 0.5543

Enzymes


UDP-glucuronosyltransferase 1-1
Name UDP-glucuronosyltransferase 1-1
Gene Name UGT1A1
Actions substrate
References
  • Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B, Ruus P, Engel J, Tukey RH, Kronbach T: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999 May;27(5):605-12. - Pubmed
  • Borlak J, Gasparic A, Locher M, Schupke H, Hermann R: N-Glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Metabolism. 2006 Jun;55(6):711-21. - Pubmed
DTHybrid score 0.4467
UDP-glucuronosyltransferase 1-3
Name UDP-glucuronosyltransferase 1-3
Gene Name UGT1A3
Actions substrate
References
  • Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B, Ruus P, Engel J, Tukey RH, Kronbach T: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999 May;27(5):605-12. - Pubmed
DTHybrid score 0.4428
UDP-glucuronosyltransferase 1-4
Name UDP-glucuronosyltransferase 1-4
Gene Name UGT1A4
Actions substrate
References
  • Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B, Ruus P, Engel J, Tukey RH, Kronbach T: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999 May;27(5):605-12. - Pubmed
DTHybrid score 0.409
UDP-glucuronosyltransferase 1-9
Name UDP-glucuronosyltransferase 1-9
Gene Name UGT1A9
Actions substrate
References
  • Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B, Ruus P, Engel J, Tukey RH, Kronbach T: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999 May;27(5):605-12. - Pubmed
DTHybrid score 0.4904
Cytochrome P450 2A6
Name Cytochrome P450 2A6
Gene Name CYP2A6
Actions inhibitor
References
  • Orhan G, Wuttke TV, Nies AT, Schwab M, Lerche H: Retigabine/Ezogabine, a KCNQ/K(V)7 channel opener: pharmacological and clinical data. Expert Opin Pharmacother. 2012 Aug;13(12):1807-16. doi: 10.1517/14656566.2012.706278. Epub 2012 Jul 12. - Pubmed
DTHybrid score 0.4233
Arylamine N-acetyltransferase 2
Name Arylamine N-acetyltransferase 2
Gene Name NAT2
Actions substrate
References
  • Amabile CM, Vasudevan A: Ezogabine: a novel antiepileptic for adjunctive treatment of partial-onset seizures. Pharmacotherapy. 2013 Feb;33(2):187-94. doi: 10.1002/phar.1185. - Pubmed
DTHybrid score 0.3941

Predictions


Id Partner name Gene Name Score
4757 Cytochrome P450 2C9 CYP2C9 0.1914
4512 Cytochrome P450 3A4 CYP3A4 0.1861
20 Prostaglandin G/H synthase 1 PTGS1 0.1767
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.1626
4924 Cytochrome P450 2C8 CYP2C8 0.1593
1588 Multidrug resistance protein 1 ABCB1 0.1447
290 Prostaglandin G/H synthase 2 PTGS2 0.1361
4200 Cytochrome P450 1A2 CYP1A2 0.1317
6016 Cytochrome P450 2C19 CYP2C19 0.1262
1729 Solute carrier family 22 member 6 SLC22A6 0.1065
275 Arachidonate 5-lipoxygenase ALOX5 0.1063
4119 Cytochrome P450 2D6 CYP2D6 0.098
6013 Cytochrome P450 2E1 CYP2E1 0.098
6030 Cytochrome P450 2B6 CYP2B6 0.0942
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0903
587 Serum albumin ALB 0.0856
4118 Cytochrome P450 3A5 CYP3A5 0.0786
6177 UDP-glucuronosyltransferase 1-10 UGT1A10 0.0715
6024 Cytochrome P450 1A1 CYP1A1 0.07
3802 Sodium channel protein type 2 subunit alpha SCN2A 0.0621
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0597
6107 Cytochrome P450 3A7 CYP3A7 0.0537
6106 Cytochrome P450 2C18 CYP2C18 0.0518
6181 UDP-glucuronosyltransferase 1-8 UGT1A8 0.0494
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0436
6180 UDP-glucuronosyltransferase 2B4 UGT2B4 0.0422
2164 Multidrug resistance-associated protein 4 ABCC4 0.0421
6103 Arylamine N-acetyltransferase 1 NAT1 0.0414
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.039
3810 Catechol O-methyltransferase COMT 0.0365
3997 Cytochrome P450 24A1, mitochondrial CYP24A1 0.0331
3804 Sodium channel protein type 4 subunit alpha SCN4A 0.0322
862 Multidrug resistance-associated protein 1 ABCC1 0.032
238 Peroxisome proliferator-activated receptor gamma PPARG 0.032
137 FolC bifunctional protein [Includes: Folylpolyglutamate synthase folC 0.0305
5880 Thrombopoietin receptor MPL 0.0303
389 Amiloride-sensitive cation channel 2, neuronal ACCN2 0.0303
467 Delta-type opioid receptor OPRD1 0.0295
696 Kappa-type opioid receptor OPRK1 0.0295
891 Dihydropteroate synthase folP 0.0276
5359 Dihydropteroate synthase folP 0.0276
7175 Dihydropteroate synthase sulI 0.0276
6142 Solute carrier family 22 member 8 SLC22A8 0.0274
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0267
6026 Alcohol dehydrogenase 6 ADH6 0.0266
518 Peroxidase/catalase T katG 0.0266
856 Vitamin D3 receptor VDR 0.0264
838 Inosine-5'-monophosphate dehydrogenase 1 IMPDH1 0.0258
796 Inosine-5'-monophosphate dehydrogenase 2 IMPDH2 0.0257
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0256
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0256
1192 Sulfotransferase 1A1 SULT1A1 0.0255
2981 Phospholipase A2, membrane associated PLA2G2A 0.025
1024 Solute carrier family 22 member 11 SLC22A11 0.0246
70 Type-1 angiotensin II receptor AGTR1 0.0238
3811 Cytochrome P450 19A1 CYP19A1 0.0235
4604 Liver carboxylesterase 1 CES1 0.0232
847 Mu-type opioid receptor OPRM1 0.0227
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0217
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0204
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0204
502 5-hydroxytryptamine 2A receptor HTR2A 0.0203
492 Histamine H1 receptor HRH1 0.0202
3601 Dihydropteroate synthase 1 folP1 0.02
3807 Dihydropteroate synthase 1 folP1 0.02
3808 Dihydropteroate synthase 2 folP2 0.02
530 Gamma-aminobutyric-acid receptor subunit alpha-4 GABRA4 0.0191
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.019
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.019
734 D1 dopamine receptor-interacting protein calcyon CALY 0.0187
373 Transthyretin TTR 0.0186
766 Beta-2 adrenergic receptor ADRB2 0.0185
556 Alpha-1A adrenergic receptor ADRA1A 0.0181
368 Enoyl-[acyl-carrier-protein] reductase [NADH] inhA 0.018
3228 Enoyl-[acyl-carrier-protein] reductase [NADH] fabI 0.018
3678 Enoyl-[acyl-carrier-protein] reductase [NADH] fabI 0.018
6856 Enoyl-[acyl-carrier-protein] reductase [NADH] fabI 0.018
580 Gamma-aminobutyric-acid receptor subunit alpha-3 GABRA3 0.018
523 Gamma-aminobutyric-acid receptor subunit alpha-5 GABRA5 0.018
6859 Protein S100-A4 S100A4 0.018
423 Gamma-aminobutyric-acid receptor subunit alpha-2 GABRA2 0.018
1275 Estrogen sulfotransferase SULT1E1 0.0177
26 Vascular endothelial growth factor receptor 3 FLT4 0.0174
590 5-hydroxytryptamine 2C receptor HTR2C 0.0173
1898 Cytochrome P450 1B1 CYP1B1 0.0173
230 ATP-binding cassette transporter sub-family C member 8 ABCC8 0.0173
776 Bile salt export pump ABCB11 0.017
1050 Bile salt sulfotransferase SULT2A1 0.0169
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0169
4100 Gamma-aminobutyric-acid receptor subunit beta-2 GABRB2 0.0169
267 Plasminogen activator inhibitor 1 SERPINE1 0.0169
1757 Myeloperoxidase MPO 0.0168
32 Vascular endothelial growth factor receptor 1 FLT1 0.0167
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0165
831 D(2) dopamine receptor DRD2 0.0163
3866 Serum amyloid A protein SAA1 0.0163
1200 AMBP protein AMBP 0.0163
1932 Apolipoprotein E APOE 0.0163
4099 Gamma-aminobutyric-acid receptor subunit beta-3 GABRB3 0.0162
1457 Long-chain-fatty-acid--CoA ligase 4 ACSL4 0.016
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0159
6221 Steroid hormone receptor ERR1 ESRRA 0.0157
738 Monocarboxylate transporter 1 SLC16A1 0.0156
504 Mast/stem cell growth factor receptor KIT 0.0146
811 Translocator protein TSPO 0.0145
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0145
1039 Histone deacetylase 9 HDAC9 0.0143
3809 Estrogen-related receptor gamma ESRRG 0.0143
1618 High affinity nerve growth factor receptor NTRK1 0.0142
6091 Gamma-aminobutyric acid receptor subunit theta GABRQ 0.0138
890 Niemann-Pick C1-like protein 1 NPC1L1 0.0136
841 Gamma-aminobutyric-acid receptor subunit alpha-6 GABRA6 0.0135
407 Vascular endothelial growth factor receptor 2 KDR 0.0134
6143 Solute carrier family 22 member 7 SLC22A7 0.013
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0126
320 5-hydroxytryptamine 1A receptor HTR1A 0.0126
6086 Gamma-aminobutyric acid receptor subunit gamma-2 GABRG2 0.0126
6090 Gamma-aminobutyric acid receptor subunit pi GABRP 0.0126
6092 Gamma-aminobutyric acid receptor subunit rho-2 GABRR2 0.0126
6088 Gamma-aminobutyric acid receptor subunit gamma-3 GABRG3 0.0126
6115 Gamma-aminobutyric acid receptor subunit rho-3 GABRR3 0.0125
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.0124
6093 Gamma-aminobutyric acid receptor subunit delta GABRD 0.0124
6089 Gamma-aminobutyric acid receptor subunit epsilon GABRE 0.0124
6087 Gamma-aminobutyric acid receptor subunit gamma-1 GABRG1 0.0124
142 Gamma-aminobutyric-acid receptor subunit rho-1 GABRR1 0.0124
630 Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial ACADSB 0.0123
465 Calmodulin CALM1 0.0123
182 2-oxoglutarate dehydrogenase E1 component, mitochondrial OGDH 0.0122
118 Organic cation/carnitine transporter 2 SLC22A5 0.0121
4098 Gamma-aminobutyric-acid receptor subunit beta-1 GABRB1 0.012
1760 Aminopeptidase N ANPEP 0.0119
6843 Aminopeptidase N pepN 0.0119
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0117
117 Sterol O-acyltransferase 1 SOAT1 0.0117
824 Sodium-dependent serotonin transporter SLC6A4 0.0115
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0114
6179 UDP-glucuronosyltransferase 2B17 UGT2B17 0.0112
6014 Cytochrome P450 2A13 CYP2A13 0.0109
318 Alpha-2A adrenergic receptor ADRA2A 0.0109
228 Beta platelet-derived growth factor receptor PDGFRB 0.0109
459 Retinoic acid receptor RXR-alpha RXRA 0.0109
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0106
2021 Thrombomodulin THBD 0.0105
170 Succinate semialdehyde dehydrogenase, mitochondrial ALDH5A1 0.0105
4132 Chloride channel protein ClC-Ka CLCNKA 0.0104
146 Androgen receptor AR 0.0104
341 5-hydroxytryptamine 3 receptor HTR3A 0.0104
3947 Xanthine dehydrogenase/oxidase XDH 0.0103
6147 Solute carrier family 22 member 3 SLC22A3 0.0095
40 RAF proto-oncogene serine/threonine-protein kinase RAF1 0.0095
319 Opioid receptor, sigma 1 OPRS1 0.0094
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0094
716 5-hydroxytryptamine 7 receptor HTR7 0.0093
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0093
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0093
280 4-aminobutyrate aminotransferase, mitochondrial ABAT 0.0093
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0093
1630 Integrin beta-2 ITGB2 0.0092
638 D(3) dopamine receptor DRD3 0.0091
243 Ribosyldihydronicotinamide dehydrogenase [quinone] NQO2 0.0091
450 Muscarinic acetylcholine receptor M4 CHRM4 0.009
4177 Proto-oncogene tyrosine-protein kinase receptor ret RET 0.0089
1256 5-hydroxytryptamine 6 receptor HTR6 0.0086
136 Estrogen receptor ESR1 0.0086
1629 Transcription factor AP-1 JUN 0.0084
6085 Fatty acid-binding protein, intestinal FABP2 0.0083
3854 Basic fibroblast growth factor receptor 1 FGFR1 0.0083
23 D(1A) dopamine receptor DRD1 0.0082
6136 Multidrug resistance-associated protein 5 ABCC5 0.0082
698 B-Raf proto-oncogene serine/threonine-protein kinase BRAF 0.0081
885 5-hydroxytryptamine 1B receptor HTR1B 0.008
6141 Sodium/bile acid cotransporter SLC10A1 0.0078
468 Cytochrome P450 4A11 CYP4A11 0.0077
6044 Serum paraoxonase/lactonase 3 PON3 0.0074
17 Proto-oncogene tyrosine-protein kinase ABL1 ABL1 0.0074
950 Alpha platelet-derived growth factor receptor PDGFRA 0.0073
1792 Tissue-type plasminogen activator PLAT 0.0073
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0072
869 Estrogen receptor beta ESR2 0.0072
273 Apoptosis regulator Bcl-2 BCL2 0.0071
102 DNA topoisomerase I, mitochondrial TOP1MT 0.007
432 D(4) dopamine receptor DRD4 0.0069
6031 Cytochrome P450 3A43 CYP3A43 0.0069
572 Integrin alpha-L ITGAL 0.0069
378 Alpha-2C adrenergic receptor ADRA2C 0.0067
629 Alpha-2B adrenergic receptor ADRA2B 0.0065
2230 Catalase CAT 0.0065
3249 Catalase katA 0.0065
3625 Catalase katA 0.0065
4539 Catalase katA 0.0065
4941 Catalase katB 0.0065
1284 Nuclear receptor subfamily 1 group I member 2 NR1I2 0.0065
6500 Phospholipase A2 PLA2G1B 0.0063
4122 Histone deacetylase 2 HDAC2 0.0063
54 Prothrombin F2 0.0063
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0063
489 Monocarboxylate transporter 2 SLC16A7 0.0062
5798 Mitogen-activated protein kinase 11 MAPK11 0.0061
723 Cytosolic phospholipase A2 PLA2G4A 0.0061
789 Alpha-1D adrenergic receptor ADRA1D 0.0061
3937 Fatty-acid amide hydrolase FAAH 0.006
6144 Solute carrier family 22 member 2 SLC22A2 0.006
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.006
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0059
4238 50S ribosomal protein L4 rplD 0.0059
5578 50S ribosomal protein L4 rplD 0.0059
6173 50S ribosomal protein L4 rplD 0.0059
6219 50S ribosomal protein L4 rplD 0.0059
1353 DNA topoisomerase 1 TOP1 0.0059
3552 DNA topoisomerase 1 topA 0.0059
436 5-hydroxytryptamine 2B receptor HTR2B 0.0056
528 5-hydroxytryptamine 1E receptor HTR1E 0.0055
4237 50S ribosomal protein L22 rplV 0.0054
6145 Solute carrier family 22 member 1 SLC22A1 0.0054
6220 Aryl hydrocarbon receptor AHR 0.0053
6017 Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1 0.0052
6137 Multidrug resistance-associated protein 6 ABCC6 0.0052
4752 Peroxisomal trans-2-enoyl-CoA reductase PECR 0.0052
2751 Holliday junction ATP-dependent DNA helicase ruvB ruvB 0.0052
4755 Holliday junction ATP-dependent DNA helicase ruvB ruvB 0.0052
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0051
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0051
610 Calcium-activated potassium channel subunit alpha 1 KCNMA1 0.005
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.005
241 Calcium-transporting ATPase type 2C member 1 ATP2C1 0.0048
844 Epidermal growth factor receptor EGFR 0.0048
6288 Low molecular weight phosphotyrosine protein phosphatase ACP1 0.0048
982 Cocaine- and amphetamine-regulated transcript protein CARTPT 0.0047
6832 Serine/threonine-protein kinase SRPK2 SRPK2 0.0046
936 Ephrin type-A receptor 2 EPHA2 0.0046
164 Histamine H4 receptor HRH4 0.0046
6042 Prostaglandin reductase 2 PTGR2 0.0046
124 Histamine H2 receptor HRH2 0.0046
5787 Angiopoietin-1 receptor TEK 0.0046
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0046
537 ATP synthase delta chain, mitochondrial ATP5D 0.0046
165 FL cytokine receptor FLT3 0.0046
251 Alcohol dehydrogenase 1A ADH1A 0.0045
823 Fibroblast growth factor receptor 2 FGFR2 0.0044
559 NADH-ubiquinone oxidoreductase chain 1 MT-ND1 0.0044
482 Glycine receptor subunit alpha-1 GLRA1 0.0043
4692 A/G-specific adenine glycosylase mutY 0.0043
193 Beta-1 adrenergic receptor ADRB1 0.0043
6043 Putative G-protein coupled receptor 44 GPR44 0.0042
4606 Purine trans deoxyribosylase ptd 0.0042
725 5-hydroxytryptamine 1D receptor HTR1D 0.0042
3941 Amine oxidase [flavin-containing] A MAOA 0.0041
3939 Amine oxidase [flavin-containing] B MAOB 0.0041
6045 Voltage-dependent calcium channel subunit alpha-2/delta-3 CACNA2D3 0.0041
3679 MTA/SAH nucleosidase mtnN 0.004
1958 S-methyl-5-thioadenosine phosphorylase MTAP 0.004
444 Alcohol dehydrogenase 1B ADH1B 0.004
775 Acetyl-CoA carboxylase 2 ACACB 0.004
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0039
128 Adenine phosphoribosyltransferase APRT 0.0038
705 Glutamate receptor 1 GRIA1 0.0038
713 Sodium-dependent dopamine transporter SLC6A3 0.0038
762 Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNA2D1 0.0037
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0037
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0037
3856 Fibroblast growth factor receptor 3 FGFR3 0.0037
462 Intermediate conductance calcium-activated potassium channel protein 4 KCNN4 0.0036
3923 Cholinesterase BCHE 0.0036
1636 Trace amine-associated receptor 1 TAAR1 0.0036
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0036
1313 Lactoylglutathione lyase GLO1 0.0036
817 DNA topoisomerase 2-alpha TOP2A 0.0035
6155 ATP-binding cassette transporter sub-family C member 11 ABCC11 0.0035
2450 Tyrosine-protein kinase ITK/TSK ITK 0.0035
517 Alcohol dehydrogenase 1C ADH1C 0.0035
6023 Cytochrome P450 11B2, mitochondrial CYP11B2 0.0034
952 Dipeptidyl peptidase 4 DPP4 0.0034
871 Glucocorticoid receptor NR3C1 0.0034
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0033
232 Corticosteroid-binding globulin SERPINA6 0.0032
778 Cysteinyl leukotriene receptor 1 CYSLTR1 0.0032
2298 Cytochrome P450-cam camC 0.0031
106 Cannabinoid receptor 2 CNR2 0.0031
260 Cytochrome P450 51 ERG11 0.0031
761 Cytochrome P450 51 ERG11 0.0031
3163 Cytochrome P450 51 cyp51 0.0031
6148 Multidrug resistance-associated protein 7 ABCC10 0.0031
6206 DNA-directed RNA polymerase subunit beta' rpoC 0.0031
2264 Nicotinate-nucleotide--dimethylbenzimidazole phosphoribosyltransferase cobT 0.0031
6174 50S ribosomal protein L32 rpmF 0.0031
80 Peroxisome proliferator-activated receptor alpha PPARA 0.003
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.003
4095 Neuronal acetylcholine receptor subunit alpha-7 CHRNA7 0.003
947 Neuronal acetylcholine receptor subunit alpha-4 CHRNA4 0.003
5878 Alpha-7 nicotinic cholinergic receptor subunit CHRFAM7A 0.0029
3932 Glutathione S-transferase A2 GSTA2 0.0029
68 Cannabinoid receptor 1 CNR1 0.0029
563 Thyroid peroxidase TPO 0.0029
131 Synaptic vesicular amine transporter SLC18A2 0.0029
284 DNA-directed RNA polymerase beta chain rpoB 0.0029
5773 DNA-directed RNA polymerase beta chain rpoB 0.0029
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0029
84 Nuclear receptor 0B1 NR0B1 0.0026
632 Alpha-1B adrenergic receptor ADRA1B 0.0026
760 Fibroblast growth factor 1 FGF1 0.0025
4192 DNA topoisomerase 2-beta TOP2B 0.0024
3917 Methylenetetrahydrofolate reductase MTHFR 0.0024
918 Glutamate receptor, ionotropic kainate 2 GRIK2 0.0023
908 Glutathione S-transferase theta-1 GSTT1 0.0023
1974 Oligopeptide transporter, kidney isoform SLC15A2 0.0022
921 Glutamate receptor 2 GRIA2 0.0021
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0021
400 Coagulation factor IX F9 0.002
5461 Coagulation factor IX F9 0.002
380 Cytochrome P450 17A1 CYP17A1 0.002
477 DNA topoisomerase 4 subunit A parC 0.002
886 DNA topoisomerase 4 subunit A parC 0.002
6226 DNA topoisomerase 4 subunit A parC 0.002
4226 Uridine phosphorylase 2 UPP2 0.0019
4217 Telomerase reverse transcriptase TERT 0.0019
404 DNA gyrase subunit A gyrA 0.0019
6224 DNA gyrase subunit A gyrA 0.0019
94 5-hydroxytryptamine 4 receptor HTR4 0.0019
904 Glutathione S-transferase P GSTP1 0.0019
511 5-hydroxytryptamine 1F receptor HTR1F 0.0019
4081 Vitamin K epoxide reductase complex subunit 1-like protein 1 VKORC1L1 0.0018
604 Vitamin K-dependent protein Z PROZ 0.0018
6046 Voltage-gated calcium channel beta 1 subunit splice variant CavB1d CACNB1 0.0018
4225 Uridine phosphorylase 1 UPP1 0.0018
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0017
719 Retinoic acid receptor responder protein 1 RARRES1 0.0017
770 Retinoic acid-induced protein 3 GPRC5A 0.0017
1995 Sodium channel protein type 9 subunit alpha SCN9A 0.0017
1245 Vitamin K-dependent protein S PROS1 0.0017
422 Vitamin K-dependent protein C PROC 0.0017
413 Amidophosphoribosyltransferase PPAT 0.0017
2515 Amidophosphoribosyltransferase purF 0.0017
3714 Amidophosphoribosyltransferase purF 0.0017
2320 Thymidine kinase, cytosolic TK1 0.0015
448 Vitamin K-dependent gamma-carboxylase GGCX 0.0015
569 Retinal dehydrogenase 2 ALDH1A2 0.0015
7 Nitric oxide synthase, inducible NOS2 0.0014
1768 Guanine nucleotide-binding protein G(I)/G(S)/G(O) gamma-2 subunit GNG2 0.0014
1581 G protein-activated inward rectifier potassium channel 2 KCNJ6 0.0014
611 Retinal dehydrogenase 1 ALDH1A1 0.0014
1268 Neuropeptide S receptor NPSR1 0.0014
1571 G protein-activated inward rectifier potassium channel 1 KCNJ3 0.0014
6931 Calcium-activated potassium channel subunit beta-1 KCNMB1 0.0014
6932 Calcium-activated potassium channel subunit beta-3 KCNMB3 0.0014
6933 Calcium-activated potassium channel subunit beta-4 KCNMB4 0.0014
6934 Small conductance calcium-activated potassium channel protein 1 KCNN1 0.0014
6935 Small conductance calcium-activated potassium channel protein 2 KCNN2 0.0014
6936 Small conductance calcium-activated potassium channel protein 3 KCNN3 0.0014
798 Osteocalcin BGLAP 0.0014
3639 Thymidine phosphorylase deoA 0.0014
3936 Thymidine phosphorylase TYMP 0.0014
564 Cellular retinoic acid-binding protein 1 CRABP1 0.0013
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0013
5934 Cytochrome P450 26A1 CYP26A1 0.0013
1302 Dihydropyrimidine dehydrogenase [NADP+] DPYD 0.0013
1010 Cytochrome P450 51A1 CYP51A1 0.0013
859 Cellular retinoic acid-binding protein 2 CRABP2 0.0013
198 Sodium channel protein type 10 subunit alpha SCN10A 0.0013
756 Sex hormone-binding globulin SHBG 0.0013
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0013
787 Vitamin K epoxide reductase complex subunit 1 VKORC1 0.0013
833 Organic cation/carnitine transporter 1 SLC22A4 0.0013
6073 Potassium channel subfamily K member 9 KCNK9 0.0012
6072 Potassium channel subfamily K member 3 KCNK3 0.0012
1360 Sphingomyelin phosphodiesterase SMPD1 0.0012
369 Coagulation factor VII F7 0.0012
780 Retinoic acid receptor RXR-gamma RXRG 0.0012
5463 Calcium-activated potassium channel subunit beta 2 KCNMB2 0.0012
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0011
24 Thymidylate synthase TMP1 0.0011
359 Thymidylate synthase TYMS 0.0011
2626 Thymidylate synthase thyA 0.0011
2729 Thymidylate synthase thyA 0.0011
5352 Thymidylate synthase THYA 0.0011
88 Retinoic acid receptor RXR-beta RXRB 0.0011
162 Retinoic acid receptor gamma-1 RARG 0.0011
6082 Neuronal acetylcholine receptor subunit beta-3 CHRNB3 0.0011
6080 Neuronal acetylcholine receptor subunit alpha-5 CHRNA5 0.0011
948 Neuronal acetylcholine receptor subunit beta-2 CHRNB2 0.0011
469 Annexin A1 ANXA1 0.0011
6020 Aldehyde oxidase AOX1 0.001
2157 NAD(P)H dehydrogenase [quinone] 1 NQO1 0.001
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.001
4097 Neuronal acetylcholine receptor subunit alpha-9 CHRNA9 0.001
6081 Neuronal acetylcholine receptor subunit alpha-6 CHRNA6 0.001
737 Mineralocorticoid receptor NR3C2 0.001
514 Potassium voltage-gated channel subfamily H member 6 KCNH6 0.001
772 Potassium voltage-gated channel subfamily H member 7 KCNH7 0.001
2207 Rhodopsin RHO 0.0009
295 Carbonic anhydrase 1 CA1 0.0009
239 Coagulation factor X F10 0.0009
6078 Neuronal acetylcholine receptor subunit beta-4 CHRNB4 0.0009
6432 Transporter snf 0.0009
614 Progesterone receptor PGR 0.0009
458 Neuronal acetylcholine receptor subunit alpha-10 CHRNA10 0.0008
6152 Solute carrier organic anion transporter family member 2A1 SLCO2A1 0.0007
291 Nitric-oxide synthase, endothelial NOS3 0.0007
813 Neuronal acetylcholine receptor subunit alpha-2 CHRNA2 0.0007
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