PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
topiramate

2D structure

Overview

Generic Names: Tipiramate [French]; Tipiramato [Spanish]; Topiramato [INN-Spanish]; Topiramatum [INN-Latin]; Topiramic acid; topiramate tablet
Trade Names: Topamax; Topamax Sprinkle
PharmGKB Accession Id: PA451728

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 (source: Drug Bank)

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. (source: Drug Bank)

ATC Therapeutic Category

  • N03AX:Other antiepileptics

Pharmacology, Interactions, and Contraindications

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 GABA<sub>A</sub> 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 glutamat 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. (source: Drug Bank)

Pharmacology

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. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

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. (source: Drug Bank)

Protein Binding

15-41% (over the blood concentration range of 0.5 - 250 mg/mL). (source: Drug Bank)

Absorption

Rapid with pleak plasma concentrations occurring after 2 hours and a bioavailability of 80%. (source: Drug Bank)

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. (source: Drug Bank)

Isomeric SMILES Code:

CC1(O[C@@H]2CO[C@@]3([C@H]([C@@H]2O1)OC(O3)(C)C)COS(=O)(=O)N)C (source: Drug Bank)

Curated Annotations (Curated Annotation)

  1. rs2304016 at chr2:165876749 in SCN2A, SCN2A2
    The A allele of this SNP was associated with resistance to sodium channel-blocking anti-epileptic drugs in a Chinese patient population.
    Variant Name:
    SCN2A:IVS7-32A>G
    Related Drugs:
    carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate
    Related Diseases:
    Epilepsy
    Evidence:
    PMID:18784617
  2. rs2032582 at chr7:86998554 in ABCB1
    This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).
    Variant Name:
    ABCB1: 2677T/A>G
    Related Drugs:
    carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin
    Related Diseases:
    Epilepsy
    Evidence:
    PMID:19450124
  3. rs3789243 at chr7:87058822 in ABCB1
    This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).
    Related Drugs:
    carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin
    Related Diseases:
    Epilepsy
    Evidence:
    PMID:19450124
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
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Variants
No phenotype data No genotype data Literature annotations available Not annotated
SCN2A
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  •   
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Variants
No phenotype data No genotype data No literature annotations Not annotated
SCN2A2
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Variants

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
CA2 Uncurated Annotation (source: Drug Bank)
CA4 Uncurated Annotation (source: Drug Bank)
GABRA1 Uncurated Annotation (source: Drug Bank)
GRIK1 Uncurated Annotation (source: Drug Bank)
SCN1A Uncurated Annotation (source: Drug Bank)

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Epilepsy
  •   
  • PD
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  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Epilepsy, Generalized
  •   
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Publications
No phenotype data No genotype data Literature annotations available Not annotated
Migraine without Aura
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  • PD
  •   
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  •   
Publications

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00273
KEGG Compound ID:
C07502
KEGG Drug ID:
D00537
PubChem Compound ID:
5284627
PubChem Substance ID:
194321

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
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