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targets (5) enzymes (2)
for drugs
Identification
Name Topiramate
Accession Number DB00273 (APRD00237)
Type small molecule
Groups approved
Description

Topiramate (brand name Topamax) is an anticonvulsant drug produced by Ortho-McNeil Neurologics, a division of Johnson & Johnson. It is used to treat epilepsy in both children and adults. In children it is also indicated for treatment of Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays). It is also Food and Drug Administration (FDA) approved for, and now most frequently prescribed for, the prevention of migraines. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Tipiramate [French]
  • Tipiramato [Spanish]
  • topiramate tablet
  • Topiramato [INN-Spanish]
  • Topiramatum [INN-Latin]
  • Topiramic acid
Brand names
  • Topamax
  • Topamax Sprinkle
Brand name mixtures Not Available
Categories
  • Anticonvulsants
  • Anti-Obesity Agents
  • Neuroprotective Agents
CAS number 97240-79-4
Weight Average: 339.362
Monoisotopic: 339.098787343
Chemical Formula C12H21NO8S
InChI Key InChIKey=KJADKKWYZYXHBB-XBWDGYHZSA-N
InChI
InChI=1S/C12H21NO8S/c1-10(2)18-7-5-16-12(6-17-22(13,14)15)9(8(7)19-10)20-11(3,4)21-12/h7-9H,5-6H2,1-4H3,(H2,13,14,15)/t7-,8-,9+,12+/m1/s1
Plain Text
IUPAC Name
[(1R,2S,6S,9R)-4,4,11,11-tetramethyl-3,5,7,10,12-pentaoxatricyclo[7.3.0.0^{2,6}]dodecan-6-yl]methyl sulfamate
SMILES
[H][C@@]12CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@]3([H])[C@]1([H])OC(C)(C)O2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbohydrates
Substructures
  • Glycerol and Derivatives
  • Pyrans
  • Acetals and Derivatives
  • Sulfuric Acids and Derivatives
  • Sulfonyls
  • Carbohydrates
  • Ethers
  • Dioxoles
  • Heterocyclic compounds
Pharmacology
Indication Used for the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures and also for the prevention of migraine headaches. In children it is also used for treatment of Lennox-Gastaut syndrome.
Pharmacodynamics Topiramate is an anticonvulsant indicated in the treatment of epilepsy and migraine. Topiramate enhances GABA-activated chloride channels. In addition, topiramate inhibits excitatory neurotransmission, through actions on kainate and AMPA receptors. There is evidence that topiramate has a specific effect on GluR5 kainate receptors. It is also an inhibitor of carbonic anhydrase, particular subtypes II and IV, but this action is weak and unlikely to be related to its anticonvulsant actions, but may account for the bad taste and the development of renal stones seen during treatment. Its possible effect as a mood stabilizer seems to occur before anticonvulsant qualities at lower dosages. Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as partial and secundarily generalized tonic-clonic seizures in the kindling model, findings predective of a broad spectrum of antiseizure activities clinically.
Mechanism of action The precise mechanism of action of topiramate is not known. However, studies have shown that topiramate blocks the action potentials elicited repetitively by a sustained depolarization of the neurons in a time-dependent manner, suggesting a state-dependent sodium channel blocking action. Topiramate also augments the activity of the neurotransmitter gamma-aminobutyrate (GABA) at some subtypes of the GABAA receptor (controls an integral chloride channel), indicating a possible mechanism through potentiation of the activity of GABA. Topiramate also demonstrates antagonism of the AMPA/kainate subtype of the glutamate excitatory amino acid receptor. It also inhibits carbonic anhydrase (particularly isozymes II and IV), but this action is weak and unlikely to be related to its anticonvulsant actions.
Absorption Rapid with pleak plasma concentrations occurring after 2 hours and a bioavailability of 80%.
Volume of distribution Not Available
Protein binding 15-41% (over the blood concentration range of 0.5 - 250 mg/mL).
Metabolism

Not extensively metabolized, 70% of the dose is eliminated unchanged in the urine. The other 30% is metabolized hepatically to six metabolites (formed by hydroxylation, hydrolysis, and glucuronidation), none of which constitute more than 5% of an administered dose.
Route of elimination Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose).
Half life 19 to 23 hours
Clearance
  • Oral plasma cl=20 – 30 mL/min [in humans following oral administration]
Toxicity Symptoms of overdose include abdominal pain, agitation, blurred vision, convulsions, depression, dizziness, double vision, drowsiness, impaired coordination, impaired mental activity, low blood pressure, reduced consciousness, severe diarrhea, sluggishness, and speech problems.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Ortho mcneil janssen pharmaceuticals inc
  • Barr laboratories inc
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Zydus pharmaceuticals usa inc
  • Accord healthcare inc
  • Apotex inc etobicoke site
  • Aurobindo pharma ltd
  • Cipla ltd
  • Glenmark generics ltd
  • Invagen pharmaceuticals inc
  • Pliva hrvatska doo
  • Ranbaxy laboratories ltd
  • Roxane laboratories inc
  • Sun pharmaceutical industries ltd
  • Torrent pharmaceuticals ltd
  • Unichem laboratories ltd
  • Upsher smith laboratories inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Tablet Oral
Prices
Unit description Cost Unit
Topiramate 200 mg tablet 8.32 USD tablet
Topamax 200 mg tablet 7.68 USD tablet
Topiramate 100 mg tablet 7.11 USD tablet
Topamax 100 mg tablet 6.31 USD tablet
Topamax 50 mg tablet 5.96 USD tablet
Topiramate 50 mg tablet 5.21 USD tablet
Topiramate 25 mg Sprinkle Capsule 3.04 USD capsule
Topiramate 25 mg tablet 2.61 USD tablet
Topiramate 99.7% powder 2.59 USD g
Topiramate 15 mg Sprinkle Capsule 2.52 USD capsule
Topamax 25 mg tablet 2.46 USD tablet
Co Topiramate 200 mg Tablet 2.08 USD tablet
Mylan-Topiramate 200 mg Tablet 2.08 USD tablet
Novo-Topiramate 200 mg Tablet 2.08 USD tablet
Phl-Topiramate 200 mg Tablet 2.08 USD tablet
Pms-Topiramate 200 mg Tablet 2.08 USD tablet
Ratio-Topiramate 200 mg Tablet 2.08 USD tablet
Sandoz Topiramate 200 mg Tablet 2.08 USD tablet
Topamax Sprinkle 25 mg Capsule 1.35 USD capsule
Sandoz Topiramate 100 mg Tablet 1.31 USD tablet
Co Topiramate 100 mg Tablet 1.31 USD tablet
Mylan-Topiramate 100 mg Tablet 1.31 USD tablet
Novo-Topiramate 100 mg Tablet 1.31 USD tablet
Phl-Topiramate 100 mg Tablet 1.31 USD tablet
Pms-Topiramate 100 mg Tablet 1.31 USD tablet
Ratio-Topiramate 100 mg Tablet 1.31 USD tablet
Topamax Sprinkle 15 mg Capsule 1.29 USD capsule
Pms-Topiramate 50 mg Tablet 1.05 USD tablet
Co Topiramate 25 mg Tablet 0.69 USD tablet
Mylan-Topiramate 25 mg Tablet 0.69 USD tablet
Novo-Topiramate 25 mg Tablet 0.69 USD tablet
Phl-Topiramate 25 mg Tablet 0.69 USD tablet
Pms-Topiramate 25 mg Tablet 0.69 USD tablet
Ratio-Topiramate 25 mg Tablet 0.69 USD tablet
Sandoz Topiramate 25 mg Tablet 0.69 USD tablet
Patents
Country Patent Number Approved Expires
United States 7125560 1999-09-01 2019-09-01
United States 5998380 1995-10-13 2015-10-13
Canada 2322644 2005-07-26 2019-03-01
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility 9.8 mg/mL PhysProp
logP -0.7 PhysProp
Predicted Properties
Property Value Source
water solubility 6.80e+00 g/l ALOGPS
logP 1.29 ALOGPS
logP 0.13 ChemAxon Molconvert
logS -1.70 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 8 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 115.54 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 72.30 ChemAxon Molconvert
polarizability 32.42 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Blum D, Meador K, Biton V, Fakhoury T, Shneker B, Chung S, Mills K, Hammer A, Isojarvi J: Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy. Neurology. 2006 Aug 8;67(3):400-6. Pubmed
External Links
Resource Link
KEGG Drug D00537 Link_out
KEGG Compound C07502 Link_out
PubChem Compound 5284627 Link_out
PubChem Substance 46508334 Link_out
ChemSpider 4447672 Link_out
BindingDB 10887 Link_out
Therapeutic Targets Database DAP000137 Link_out
PharmGKB PA451728 Link_out
Drug Product Database 2239908 Link_out
RxList http://www.rxlist.com/cgi/generic2/topiram.htm Link_out
Drugs.com http://www.drugs.com/cdi/topiramate.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/top1541.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Topiramate Link_out
ATC Codes
  • N03AX11
AHFS Codes
  • 28:12.92
PDB Entries Not Available
FDA label show (235.6 KB)
MSDS show (57.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Gamma-aminobutyric-acid receptor subunit alpha-1

Pharmacological action: yes
Actions: agonist

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P14867 Link_out
Gene: GABRA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Nowakowska E, Kus K, Czubak A, Jedrzejewska J: Memory improving and antidepressant effects of topiramate in rats. Arzneimittelforschung. 2009;59(10):487-92. Pubmed
  4. Braga MF, Aroniadou-Anderjaska V, Li H, Rogawski MA: Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons. J Pharmacol Exp Ther. 2009 Aug;330(2):558-66. Epub 2009 May 5. Pubmed

2. Sodium channel protein type 1 subunit alpha

Pharmacological action: yes
Actions: inhibitor

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient

Organism class: human
UniProt ID: P35498 Link_out
Gene: SCN1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Coppola G, Capovilla G, Montagnini A, Romeo A, Spano M, Tortorella G, Veggiotti P, Viri M, Pascotto A: Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. Epilepsy Res. 2002 Mar;49(1):45-8. Pubmed
  2. Ceulemans B, Cras P: “Severe myoclonic epilepsy in infancy”. Relevance for the clinician of severe epilepsy starting in infancy. Acta Neurol Belg. 2004 Sep;104(3):95-9. Pubmed
  3. Ceulemans B, Boel M, Claes L, Dom L, Willekens H, Thiry P, Lagae L: Severe myoclonic epilepsy in infancy: toward an optimal treatment. J Child Neurol. 2004 Jul;19(7):516-21. Pubmed
  4. Korff C, Laux L, Kelley K, Goldstein J, Koh S, Nordli D Jr: Dravet syndrome (severe myoclonic epilepsy in infancy): a retrospective study of 16 patients. J Child Neurol. 2007 Feb;22(2):185-94. Pubmed
  5. Nieto Barrera M, Candau Fernandez Mensaque R, Nieto Jimenez M: [Severe myoclonic epilepsy in infancy (Dravet’s syndrome). Its nosological characteristics and therapeutic aspects] Rev Neurol. 2003 Jul 1-15;37(1):64-8. Pubmed

3. Glutamate receptor, ionotropic kainate 1

Pharmacological action: yes
Actions: antagonist

L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. May be involved in the transmission of light information from the retina to the hypothalamus. This receptor binds domoate > kainate > L-glutamate = quisqualate > CNQX = DNQX > AMPA > dihydrokainate > NMDA

Organism class: human
UniProt ID: P39086 Link_out
Gene: GRIK1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Rogawski MA, Gryder D, Castaneda D, Yonekawa W, Banks MK, Lia H: GluR5 kainate receptors, seizures, and the amygdala. Ann N Y Acad Sci. 2003 Apr;985:150-62. Pubmed
  2. Gryder DS, Rogawski MA: Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons. J Neurosci. 2003 Aug 6;23(18):7069-74. Pubmed
  3. Kaminski RM, Banerjee M, Rogawski MA: Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist. Neuropharmacology. 2004 Jun;46(8):1097-104. Pubmed
  4. Braga MF, Aroniadou-Anderjaska V, Li H, Rogawski MA: Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons. J Pharmacol Exp Ther. 2009 Aug;330(2):558-66. Epub 2009 May 5. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

4. Carbonic anhydrase 2

Pharmacological action: yes
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00918 Link_out
Gene: CA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Maryanoff BE, McComsey DF, Costanzo MJ, Hochman C, Smith-Swintosky V, Shank RP: Comparison of sulfamate and sulfamide groups for the inhibition of carbonic anhydrase-II by using topiramate as a structural platform. J Med Chem. 2005 Mar 24;48(6):1941-7. Pubmed
  2. Ma L, Huang YG, Deng YC, Tian JY, Rao ZR, Che HL, Zhang HF, Zhao G: Topiramate reduced sweat secretion and aquaporin-5 expression in sweat glands of mice. Life Sci. 2007 Jun 6;80(26):2461-8. Epub 2007 Apr 29. Pubmed
  3. Di Fiore A, Scozzafava A, Winum JY, Montero JL, Pedone C, Supuran CT, De Simone G: Carbonic anhydrase inhibitors: binding of an antiglaucoma glycosyl-sulfanilamide derivative to human isoform II and its consequences for the drug design of enzyme inhibitors incorporating sugar moieties. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1726-31. Epub 2007 Jan 8. Pubmed
  4. Casini A, Antel J, Abbate F, Scozzafava A, David S, Waldeck H, Schafer S, Supuran CT: Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with isozymes I, II and IV. Bioorg Med Chem Lett. 2003 Mar 10;13(5):841-5. Pubmed
  5. Winum JY, Scozzafava A, Montero JL, Supuran CT: Sulfamates and their therapeutic potential. Med Res Rev. 2005 Mar;25(2):186-228. Pubmed

5. Carbonic anhydrase 4

Pharmacological action: yes
Actions: inhibitor

Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4

Organism class: human
UniProt ID: P22748 Link_out
Gene: CA4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett. 2004 Jan 5;14(1):217-23. Pubmed
  2. Dodgson SJ, Shank RP, Maryanoff BE: Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia. 2000;41 Suppl 1:S35-9. Pubmed
  3. Masereel B, Rolin S, Abbate F, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties. J Med Chem. 2002 Jan 17;45(2):312-20. Pubmed
  4. Vullo D, Franchi M, Gallori E, Antel J, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. J Med Chem. 2004 Feb 26;47(5):1272-9. Pubmed
Enzymes

1. Cytochrome P450 2C19

Actions: inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:37

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.