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targets (2) enzymes (5)
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Identification
Name Mexiletine
Accession Number DB00379 (APRD00242)
Type small molecule
Groups approved
Description

Antiarrhythmic agent pharmacologically similar to lidocaine. It may have some anticonvulsant properties. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Mexiletina [INN-Spanish]
  • Mexiletine HCL
  • Mexiletinum [INN-Latin]
  • Mexilitine
Brand names
  • Mexitil
Brand name mixtures Not Available
Categories
  • Anti-Arrhythmia Agents
CAS number 31828-71-4
Weight Average: 179.2588
Monoisotopic: 179.131014171
Chemical Formula C11H17NO
InChI Key InChIKey=VLPIATFUUWWMKC-UHFFFAOYSA-N
InChI
InChI=1S/C11H17NO/c1-8-5-4-6-9(2)11(8)13-7-10(3)12/h4-6,10H,7,12H2,1-3H3
Plain Text
IUPAC Name
2-(2-aminopropoxy)-1,3-dimethylbenzene
SMILES
CC(N)COC1=C(C)C=CC=C1C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Ethers
  • Anisoles
  • Phenyl Esters
Substructures
  • Phenols and Derivatives
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Aromatic compounds
  • Anisoles
  • Phenyl Esters
Pharmacology
Indication For the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.
Pharmacodynamics Mexiletine is a local anesthetic, antiarrhythmic agent (Class Ib), structurally similar to lidocaine, but orally active. Mexiletine has fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. It shortens the action potential duration, reduces refractoriness, and decreases Vmax in partially depolarized cells with fast response action potentials. Mexiletine either does not change the action potential duration, or decreases the action potential duration.
Mechanism of action Mexiletine, like lidocaine, inhibits the inward sodium current required for the initiation and conduction of impulses, thus reducing the rate of rise of the action potential, Phase 0. It achieves this reduced sodium current by inhibiting sodium channels. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers in the heart. The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), which results in an increase in the ERP/APD ratio. It does not significantly affect resting membrane potential or sinus node automaticity, left ventricular function, systolic arterial blood pressure, atrioventricular (AV) conduction velocity, or QRS or QT intervals
Absorption Well absorbed (bioavailability 90%) from the gastrointenstinal tract.
Volume of distribution
  • 5 to 7 L/lg
Protein binding 50-60%
Metabolism

Primarily hepatic (85%) via CYP2D6 and CYP1A2 (primarily CYP2D6).

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 2D6 2-hydroxymexiletine 2-hydroxylation 22.1 44.66
Cytochrome P450 2D6 p-hydroxymexiletine p-hydroxylation 22.6 40.3
Cytochrome P450 1A2 2-hydroxymexiletine 2-hydroxylase 15.2 0.1
Cytochrome P450 1A2 p-hydroxymexiletine p-hydroxylase 13.9 0.081
Route of elimination Approximately 10% is excreted unchanged by the kidney. The urinary excretion of N-methylmexiletine in man is less than 0.5%.
Half life 10-12 hours
Clearance Not Available
Toxicity Symptoms of overdose include nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse, and coma.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00329 Mexiletine Pathway SMP00329
Pharmacoeconomics
Manufacturers
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Boehringer ingelheim
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Mexitil 250 mg capsule 1.85 USD capsule
Mexiletine HCl 250 mg capsule 1.6 USD capsule
Mexiletine 250 mg capsule 1.54 USD capsule
Mexiletine HCl 200 mg capsule 1.38 USD capsule
Mexiletine 200 mg capsule 1.33 USD capsule
Mexitil 200 mg capsule 1.23 USD capsule
Novo-Mexiletine 200 mg Capsule 1.19 USD capsule
Mexiletine HCl 150 mg capsule 1.16 USD capsule
Mexiletine 150 mg capsule 1.11 USD capsule
Novo-Mexiletine 100 mg Capsule 0.89 USD capsule
Patents Not Available
Properties
State solid
Melting point 203-205 oC
Experimental Properties
Property Value Source
water solubility 8.25 mg/mL PhysProp
logP 2.1 PhysProp
pKa 9.2 Various sources
Predicted Properties
Property Value Source
water solubility 5.38e-01 g/l ALOGPS
logP 2.17 ALOGPS
logP 2.46 ChemAxon Molconvert
logS -2.52 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 35.25 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 54.97 ChemAxon Molconvert
polarizability 21.17 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07220 Link_out
PubChem Compound 4178 Link_out
PubChem Substance 46505491 Link_out
ChemSpider 4034 Link_out
BindingDB 50117271 Link_out
ChEBI 6916 Link_out
ChEMBL 6916 Link_out
Therapeutic Targets Database DAP000505 Link_out
PharmGKB PA450488 Link_out
Drug Product Database 2230359 Link_out
RxList http://www.rxlist.com/cgi/generic3/mexiletine.htm Link_out
Drugs.com http://www.drugs.com/cdi/mexiletine.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/mex1261.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Mexiletine Link_out
ATC Codes
  • C01BB02
AHFS Codes
  • 24:04.04.08
PDB Entries Not Available
FDA label show (1.2 MB)
MSDS show (47.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take with food to reduce irritation.
Targets

1. Sodium channel protein type 5 subunit alpha

Pharmacological action: yes
Actions: inhibitor

This protein 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. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential in the electrocardiogram

Organism class: human
UniProt ID: Q14524 Link_out
Gene: SCN5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Valdivia CR, Ackerman MJ, Tester DJ, Wada T, McCormack J, Ye B, Makielski JC: A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine. Cardiovasc Res. 2002 Aug 1;55(2):279-89. Pubmed
  2. Chinushi M, Tagawa M, Sugiura H, Komura S, Hosaka Y, Washizuka T, Aizawa Y: Ventricular tachyarrhythmias in a canine model of LQT3: arrhythmogenic effects of sympathetic activity and therapeutic effects of mexiletine. Circ J. 2003 Mar;67(3):263-8. Pubmed
  3. Fabritz L, Kirchhof P, Franz MR, Nuyens D, Rossenbacker T, Ottenhof A, Haverkamp W, Breithardt G, Carmeliet E, Carmeliet P: Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice. Cardiovasc Res. 2003 Mar 15;57(4):1085-93. Pubmed
  4. Wang HW, Zheng YQ, Yang ZF, Li CZ, Liu YM: Effect of mexiletine on long QT syndrome model. Acta Pharmacol Sin. 2003 Apr;24(4):316-20. Pubmed
  5. Napolitano C, Bloise R, Priori SG: Gene-specific therapy for inherited arrhythmogenic diseases. Pharmacol Ther. 2006 Apr;110(1):1-13. Epub 2005 Sep 15. Pubmed
  6. Shimizu W, Antzelevitch C, Suyama K, Kurita T, Taguchi A, Aihara N, Takaki H, Sunagawa K, Kamakura S: Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2000 Dec;11(12):1320-9. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Aryl hydrocarbon receptor

Pharmacological action: unknown
Actions: agonist

Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues

Organism class: human
UniProt ID: P35869 Link_out
Gene: AHR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR: Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007 Jun;71(6):1475-86. Epub 2007 Feb 27. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
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
  3. Nakajima M, Kobayashi K, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y: Involvement of CYP1A2 in mexiletine metabolism. Br J Clin Pharmacol. 1998 Jul;46(1):55-62. Pubmed

2. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 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
  3. Nakajima M, Kobayashi K, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y: Involvement of CYP1A2 in mexiletine metabolism. Br J Clin Pharmacol. 1998 Jul;46(1):55-62. Pubmed

3. Cytochrome P450 2B6

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
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

4. Cytochrome P450 2E1

Actions: substrate

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
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

5. Cytochrome P450 3A4

Actions: substrate

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 April 19, 2011 15:03

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.