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Identification
NameLamotrigine
Accession NumberDB00555  (APRD00570)
Typesmall molecule
Groupsapproved, investigational
Description

Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. For epilepsy it is used to treat partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Lamotrigine also acts as a mood stabilizer. It is the first medication since lithium granted Food and Drug Administration (FDA) approval for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants, lamotrigine has relatively few side-effects and does not require blood monitoring. The exact way lamotrigine works is unknown. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazineNot AvailableNot Available
LamictalNot AvailableNot Available
LamotriginaSpanishINN
LamotrigineFrench/GermanINN
LamotriginumLatinINN
SaltsNot Available
Brand names
NameCompany
ConvulsanActavis
CrisometJuste
DafexPhoenix
DaksolPharmavita
DanoptinPliva
DezepilRafarm
ElmendosGlaxoSmithKline
EpilepaxIvax
EpimilIvax
EpiralZentiva
EpitecCipla Medpro
EpitrigineActavis
LabilenoGlaxoSmithKline
LambipolGlaxoSmithKline
LamectPharmaSwiss
LameptilSandoz
Lameptil SSandoz
LametecVitalchem
LamezIntas
LamictalGlaxoSmithKline
Lamictal CDGlaxoSmithKline
Lamictal XRGlaxoSmithKline
LamictinGlaxoSmithKline
LamotrixGlenmark
LarigRowex
MedotriginMedochemie
MogineDouglas
TrimolepPsicofarma
TrogineRanbaxy
XebarinDr Reddys
Brand mixtures
Brand NameIngredients
CionamatLamotrigine and Clonazepam
Categories
CAS number84057-84-1
WeightAverage: 256.091
Monoisotopic: 255.007850663
Chemical FormulaC9H7Cl2N5
InChI KeyPYZRQGJRPPTADH-UHFFFAOYSA-N
InChI
InChI=1S/C9H7Cl2N5/c10-5-3-1-2-4(6(5)11)7-8(12)14-9(13)16-15-7/h1-3H,(H4,12,13,14,16)
IUPAC Name
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
SMILES
NC1=NC(N)=C(N=N1)C1=C(Cl)C(Cl)=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassHalobenzenes
Direct parentDichlorobenzenes
Alternative parentsAminotriazines; Primary Aromatic Amines; Aryl Chlorides; Polyamines; Organochlorides
Substituentsaminotriazine; aryl chloride; primary aromatic amine; aryl halide; triazine; polyamine; organochloride; organohalogen; amine; primary amine; organonitrogen compound
Classification descriptionThis compound belongs to the dichlorobenzenes. These are compounds containing a benzene with exactly two chlorine atoms attached to it.
Pharmacology
IndicationFor the adjunctive treatment of partial seizures in epilepsy and generalized seizures of Lennox-Gastaut syndrome. Also for the maintenance treatment of bipolar I disorder and depression.
PharmacodynamicsLamotrigine, an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Lamotrigine is also used in the treatment of depression and bipolar disorder. Lamotrigine is thought to exert its anticonvulsant effect by stabilizing presynaptic neuronal membranes. Lamotrigine inhibits sodium currents by selectively binding to the inactivated state of the sodium channel and subsequently suppresses the release of the excilatory amino acid, glutamate.
Mechanism of actionOne proposed mechanism of action of Lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. in vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels and/or calcium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate). Studies on lamotrigine show binding to sodium channels similar to local anesthetics.
Absorption98%
Volume of distribution
  • 0.9 to 1.3 L/kg
Protein binding55%
Metabolism

Hepatic

SubstrateEnzymesProduct
Lamotrigine
lamotrigine-2-N-glucuronideDetails
Route of eliminationNot Available
Half life25 +/- 10 hours (healthy individuals); 42.9 hours (chronic renal failure)
Clearance
  • Apparent plasma cl=0.44 mL/min/kg [healthy volunteers taking single-dose LAMICTAL]
  • Apparent plasma cl=0.58 mL/min/kg [healthy volunteers taking multiple-dose LAMICTAL]
  • Apparent plasma cl=0.30 mL/min/kg [healthy volunteers taking valproate and single-dose LAMICTAL]
  • Apparent plasma cl=0.18 mL/min/kg [healthy volunteers taking valproate and multiple-dose LAMICTAL]
  • Apparent plasma cl=1.1 mL/min/kg [Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone plus valproate and single-dose LAMICTAL]
  • Apparent plasma cl=1.12 mL/min/kg [Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone plus valproate and multiple-dose LAMICTAL]
ToxicityLD50=250 (mg/kg) (in rat, mice); LD50>640 orally (mg/kg) (in rat, mice) (Sawyer). Symptoms of overdose include decreased level of consciousness, coma, delayed heartbeat, increased seizures, lack of coordination, and rolling eyeballs.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9382
Caco-2 permeable + 0.8867
P-glycoprotein substrate Non-substrate 0.7155
P-glycoprotein inhibitor I Non-inhibitor 0.911
P-glycoprotein inhibitor II Non-inhibitor 0.9604
Renal organic cation transporter Non-inhibitor 0.8176
CYP450 2C9 substrate Non-substrate 0.9162
CYP450 2D6 substrate Non-substrate 0.9055
CYP450 3A4 substrate Non-substrate 0.6862
CYP450 1A2 substrate Non-inhibitor 0.611
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.7007
CYP450 2C19 substrate Non-inhibitor 0.8594
CYP450 3A4 substrate Non-inhibitor 0.7678
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5515
Ames test Non AMES toxic 0.8202
Carcinogenicity Non-carcinogens 0.7895
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.7556 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9168
hERG inhibition (predictor II) Non-inhibitor 0.8735
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
  • Aurobindo pharma ltd
  • Dr reddys laboratories ltd
  • Glenmark generics ltd
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Taro pharmaceutical industries ltd
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Zydus pharmaceuticals usa inc
  • Smithkline beecham corp
  • Smithkline beecham corp dba glaxosmithkline
  • Apotex inc
  • Cadista pharmaceuticals inc
  • Lupin ltd
  • Matrix laboratories ltd
  • Roxane laboratories inc
  • Torrent pharmaceuticals ltd
  • Upsher smith laboratories inc
  • Wockhardt ltd
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
LaMICtal Starter 98 25 (84)-100(14)mg Kit Box556.69USDbox
LaMICtal XR 200 mg 24 Hour tablet12.11USDtablet
Lamictal xr 200 mg tablet11.65USDtablet
LaMICtal XR 100 mg 24 Hour tablet11.36USDtablet
Lamictal xr 100 mg tablet10.92USDtablet
Lamictal xr 50 mg tablet10.2USDtablet
Lamictal 200 mg tablet7.44USDtablet
Lamictal odt start kt (orange)7.28USDtablet
Lamictal xr start kit (orange)7.28USDtablet
Lamictal odt 200 mg tablet6.95USDtablet
Lamictal odt 100 mg tablet5.82USDtablet
Lamotrigine 200 mg tablet5.78USDtablet
LaMICtal 25 mg Chew Tabs5.63USDtab
Lamictal odt 50 mg tablet5.46USDtablet
Lamictal tab start kit (green)5.46USDtablet
Lamictal 150 mg tablet5.38USDtablet
Lamictal odt 25 mg tablet5.1USDtablet
Lamictal xr 25 mg tablet5.1USDtablet
Lamictal 100 mg tablet4.72USDtablet
Lamotrigine tablet starter kit4.24USDtablet
Lamotrigine 150 mg tablet3.98USDtablet
Lamictal 25 mg tablet3.78USDtablet
Lamotrigine 100 mg tablet3.52USDtablet
LamoTRIgine 25 mg Chew Tabs3.33USDtab
LamoTRIgine 5 mg Chew Tabs3.18USDtab
Lamotrigine 25 mg tablet2.9USDtablet
Apo-Lamotrigine 150 mg Tablet1.31USDtablet
Mylan-Lamotrigine 150 mg Tablet1.31USDtablet
Novo-Lamotrigine 150 mg Tablet1.31USDtablet
Pms-Lamotrigine 150 mg Tablet1.31USDtablet
Ratio-Lamotrigine 150 mg Tablet1.31USDtablet
Apo-Lamotrigine 100 mg Tablet0.88USDtablet
Mylan-Lamotrigine 100 mg Tablet0.88USDtablet
Novo-Lamotrigine 100 mg Tablet0.88USDtablet
Pms-Lamotrigine 100 mg Tablet0.88USDtablet
Ratio-Lamotrigine 100 mg Tablet0.88USDtablet
Apo-Lamotrigine 25 mg Tablet0.22USDtablet
Mylan-Lamotrigine 25 mg Tablet0.22USDtablet
Novo-Lamotrigine 25 mg Tablet0.22USDtablet
Pms-Lamotrigine 25 mg Tablet0.22USDtablet
Ratio-Lamotrigine 25 mg Tablet0.22USDtablet
Lamictal 5 mg Chewable Tablet0.18USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States56982261995-07-292012-07-29
Canada22777222001-03-272012-01-29
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point216-218 °C (uncorr)Not Available
logP2.5Not Available
Predicted Properties
PropertyValueSource
water solubility4.88e-01 g/lALOGPS
logP1.87ALOGPS
logP1.93ChemAxon
logS-2.7ALOGPS
pKa (strongest acidic)14.98ChemAxon
pKa (strongest basic)5.87ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area90.71ChemAxon
rotatable bond count1ChemAxon
refractivity66.62ChemAxon
polarizability23.1ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Grahame Roy Lee, “Process for the preparation of lamotrigine.” U.S. Patent US5925755, issued January, 1981.

US5925755
General Reference
  1. Backonja M: Neuromodulating drugs for the symptomatic treatment of neuropathic pain. Curr Pain Headache Rep. 2004 Jun;8(3):212-6. Pubmed
  2. Barbosa L, Berk M, Vorster M: A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry. 2003 Apr;64(4):403-7. Pubmed
  3. Jensen TS: Anticonvulsants in neuropathic pain: rationale and clinical evidence. Eur J Pain. 2002;6 Suppl A:61-8. Pubmed
  4. Pappagallo M: Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine. Clin Ther. 2003 Oct;25(10):2506-38. Pubmed
  5. Tehrani SP, Daryaafzoon M, Bakhtiarian A, Ejtemaeemehr S, Sahraei H: The effects of lamotrigine on the acquisition and expression of morphine-induced place preference in mice. Pak J Biol Sci. 2009 Jan 1;12(1):33-9. Pubmed
External Links
ResourceLink
KEGG DrugD00354
PubChem Compound3878
PubChem Substance46505408
ChemSpider3741
BindingDB50031299
ChEBI6367
ChEMBLCHEMBL741
Therapeutic Targets DatabaseDAP000039
PharmGKBPA450164
IUPHAR2622
Guide to Pharmacology2622
Drug Product Database2248232
RxListhttp://www.rxlist.com/cgi/generic/lamotrigine.htm
Drugs.comhttp://www.drugs.com/cdi/lamotrigine.html
WikipediaLamotrigine
ATC CodesN03AX09
AHFS Codes
  • 28:12.92
PDB EntriesNot Available
FDA labelshow(3.15 MB)
MSDSshow(28.6 KB)
Interactions
Drug Interactions
Drug
ButabarbitalBarbiturates like butabarbital may decrease the serum concentration of lamotrigine. There are separate patient management guidelines for patients age 12 and under and for patients older than 12 years of age. Monitor for decreased serum concentrations/therapeutic effects of lamotrigine if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased.
ButalbitalBarbiturates such as butalbital may decrease the serum concentration of lamotrigine. There are separate management guidelines for patients age 12 and under and for patients older than 12 years of age. Please refer to the current approved prescribing information for additional information. Monitor for decreased serum concentrations/therapeutic effects of lamotrigine if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased.
CarbamazepineLamotrigine may increase the adverse effects of carbamazepine by increasing the concentration of its active metabolite, carbamazepine-epoxide. Carbamazepine may decrease the therapeutic effect of lamotrigine by increasing its metabolism. Lamotrigine doses should be adjusted accordingly. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinue or doses are changed.
ClozapineLamotrigine increases the effect and toxicity of clozapine
DesogestrelThe oral contraceptive decreases the effect of lamotrigine
Ethinyl EstradiolThe oral contraceptive decreases the effect of lamotrigine
EthotoinPhenytoin may reduce levels of lamotrigine
EzogabineIn 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.
FosphenytoinPhenytoin may reduce levels of lamotrigine
MephenytoinPhenytoin may reduce levels of lamotrigine
MestranolThe oral contraceptive decreases the effect of lamotrigine
MethsuximideMethsuximide decreases the effect of lamotrigine
NorethindroneThe oral contraceptive decreases the effect of lamotrigine
PhenytoinPhenytoin may reduce levels of lamotrigine
RifampicinRifampin decreases levels of lamotrigine
ThiopentalThiopental may increase the metabolism and clearance of Lamotrigine. Monitor for decreased therapeutic effect of Lamotrigine if Thiopental is initiated.
TriprolidineThe CNS depressants, Triprolidine and Lamotrigine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Valproic AcidValproic acid may increase the adverse effects of Lamotrigine by increasing Lamotrigine serum concentration. The Lamotrigine dose should be reduced by 50% during concomitant therapy. Monitor for changes in Lamotrigine therapeutic and adverse effects if Valproic acid is initiated, discontinued or dose changed.
Food Interactions
  • Take without regard to meals.

Targets

1. Sodium channel protein type 2 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 2 subunit alpha Q99250 Details

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. Lipkind GM, Fozzard HA: Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels. Mol Pharmacol. 2005 Dec;68(6):1611-22. Epub 2005 Sep 20. Pubmed

Enzymes

1. UDP-glucuronosyltransferase 1-4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-4 P22310 Details

References:

  1. Argikar UA, Senekeo-Effenberger K, Larson EE, Tukey RH, Remmel RP: Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009 Nov;39(11):826-35. Pubmed
  2. Chen H, Yang K, Choi S, Fischer JH, Jeong H: Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17beta-estradiol: a potential mechanism of increased lamotrigine elimination in pregnancy. Drug Metab Dispos. 2009 Sep;37(9):1841-7. Epub 2009 Jun 22. Pubmed
  3. Argikar UA, Remmel RP: Variation in glucuronidation of lamotrigine in human liver microsomes. Xenobiotica. 2009 May;39(5):355-63. Pubmed

2. UDP-glucuronosyltransferase 1-3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-3 P35503 Details

References:

  1. Argikar UA, Remmel RP: Variation in glucuronidation of lamotrigine in human liver microsomes. Xenobiotica. 2009 May;39(5):355-63. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Luna-Tortos C, Fedrowitz M, Loscher W: Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008 Dec;55(8):1364-75. Epub 2008 Sep 11. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11