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Identification
NameClonazepam
Accession NumberDB01068  (APRD00054)
Typesmall molecule
Groupsapproved, illicit
Description

An anticonvulsant used for several types of seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop. It is seldom effective in generalized tonic-clonic or partial seizures. The mechanism of action appears to involve the enhancement of gamma-aminobutyric acid receptor responses. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
1,3-dihydro-7-Nitro-5-(2-chlorophenyl)-2H-1,4.benzodiazepin-2-oneNot AvailableNot Available
5-(2-Chloro-phenyl)-7-nitro-1,3-dihydro-benzo[e][1,4]diazepin-2-oneNot AvailableNot Available
5-(2-Chlorophenyl)-7-nitro-1H-benzo[e][1,4]diazepin-2(3H)-oneNot AvailableNot Available
5-(O-Chlorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-oneNot AvailableNot Available
CLONAZEPAMNot AvailableNot Available
ClonazepamumNot AvailableINN
SaltsNot Available
Brand names
NameCompany
AntelepsinAWD
IktorivilRoche
KlonopinRoche
RivotrilRoche
Brand mixturesNot Available
Categories
CAS number1622-61-3
WeightAverage: 315.711
Monoisotopic: 315.041068908
Chemical FormulaC15H10ClN3O3
InChI KeyDGBIGWXXNGSACT-UHFFFAOYSA-N
InChI
InChI=1S/C15H10ClN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20)
IUPAC Name
5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one
SMILES
[O-][N+](=O)C1=CC2=C(NC(=O)CN=C2C2=CC=CC=C2Cl)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzodiazepines
SubclassNot Available
Direct parentBenzodiazepines
Alternative parentsNitrobenzenes; Chlorobenzenes; Aryl Chlorides; Nitronic Acids; Secondary Carboxylic Acid Amides; Nitro Compounds; Organic Oxoazanium Compounds; Carboxylic Acids; Polyamines; Organochlorides
Substituentsnitrobenzene; chlorobenzene; aryl chloride; aryl halide; benzene; nitronic acid; secondary carboxylic acid amide; carboxamide group; nitro compound; polyamine; carboxylic acid derivative; carboxylic acid; organic oxoazanium; amine; organohalogen; organonitrogen compound; organochloride
Classification descriptionThis compound belongs to the benzodiazepines. These are organic compounds containing a benzene ring fused to either isomers of diazepine(unsaturated seven-member heterocycle with two nitrogen atoms replacing two carbon atoms).
Pharmacology
IndicationClonazepam is used as an anticonvulsant in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. It can also be used for the treatment of panic disorders.
PharmacodynamicsClonazepam, a benzodiazepine, is used primarily as an anticonvulsant in the treatment of absence seizures, petit mal variant seizures (Lennox-Gastaut syndrome), akinetic and myoclonic seizures, and nocturnal myoclonus. It enhances the activity of gamma aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the central nervous system. In animals, convulsions are antagonized occurs following administration of clonazepam. In humans, clonazepam suppresses the spike and wave discharge in absence seizures (petit mal) and decreases the frequency, amplitude, duration, and spread of discharge in minor motor seizures.
Mechanism of actionAllosteric interactions between central benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptors potentiate the effects of GABA. As GABA is an inhibitory neurotransmitter, this results in increased inhibition of the ascending reticular activating system. Benzodiazepines, in this way, block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.
AbsorptionClonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Cmax, oral administration = 1 -4 hours.
Volume of distributionNot Available
Protein binding85% bound to plasma proteins.
Metabolism

Hepatic (cytochrome P450, including CYP3A). Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated, and glucuronidated.

Route of eliminationClonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Metabolites of Klonopin are excreted by the kidneys. Clonazepam also undergoes acetylation via NAT2.
Half life30-40 hours
ClearanceNot Available
ToxicitySomnolence, confusion, coma, and diminished reflexes. The most commonly reported adverse event when clonazepam is used for seizure disorders is CNS depression. LD50, oral, rats = >15000 mg/kg.
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 + 0.9946
Blood Brain Barrier + 0.9718
Caco-2 permeable + 0.5313
P-glycoprotein substrate Substrate 0.5594
P-glycoprotein inhibitor I Non-inhibitor 0.8474
P-glycoprotein inhibitor II Non-inhibitor 0.9157
Renal organic cation transporter Non-inhibitor 0.8179
CYP450 2C9 substrate Non-substrate 0.7777
CYP450 2D6 substrate Non-substrate 0.8934
CYP450 3A4 substrate Substrate 0.7295
CYP450 1A2 substrate Inhibitor 0.7646
CYP450 2C9 substrate Inhibitor 0.5213
CYP450 2D6 substrate Non-inhibitor 0.8271
CYP450 2C19 substrate Inhibitor 0.7441
CYP450 3A4 substrate Inhibitor 0.5565
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7255
Ames test Non AMES toxic 0.6778
Carcinogenicity Non-carcinogens 0.6417
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 1.6422 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9821
hERG inhibition (predictor II) Non-inhibitor 0.8734
Pharmacoeconomics
Manufacturers
  • Barr laboratories inc
  • Par pharmaceutical inc
  • Hoffmann la roche inc
  • Actavis elizabeth llc
  • Alphapharm party ltd
  • Apotex inc
  • Caraco pharmaceutical laboratories ltd
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Vintage pharmaceuticals inc
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
TabletOral0.5 mg, 1 mg, 2 mg
Prices
Unit descriptionCostUnit
Klonopin 2 mg tablet2.85USDtablet
Klonopin 1 mg tablet2.17USDtablet
Klonopin 0.5 mg tablet1.91USDtablet
ClonazePAM ODT 2 mg Dispersible Tablet1.67USDdispersible tablet
ClonazePAM ODT 0.25 mg Dispersible Tablet1.22USDdispersible tablet
ClonazePAM ODT 0.5 mg Dispersible Tablet1.18USDdispersible tablet
ClonazePAM ODT 0.125 mg Dispersible Tablet1.17USDdispersible tablet
ClonazePAM ODT 1 mg Dispersible Tablet1.1USDdispersible tablet
Clonazepam 2 mg tablet0.81USDtablet
Clonazepam 1 mg tablet0.63USDtablet
Clonazepam 0.5 mg tablet0.61USDtablet
Rivotril 2 mg Tablet0.38USDtablet
Rivotril 0.5 mg Tablet0.22USDtablet
Apo-Clonazepam 2 mg Tablet0.21USDtablet
Co Clonazepam 2 mg Tablet0.21USDtablet
Mylan-Clonazepam 2 mg Tablet0.21USDtablet
Novo-Clonazepam 2 mg Tablet0.21USDtablet
Phl-Clonazepam 2 mg Tablet0.21USDtablet
Pms-Clonazepam 2 mg Tablet0.21USDtablet
Ratio-Clonazepam 2 mg Tablet0.21USDtablet
Sandoz Clonazepam 2 mg Tablet0.21USDtablet
Co Clonazepam 1 mg Tablet0.19USDtablet
Phl-Clonazepam 1 mg Tablet0.19USDtablet
Pms-Clonazepam 1 mg Tablet0.19USDtablet
Sandoz Clonazepam 1 mg Tablet0.19USDtablet
Apo-Clonazepam 0.5 mg Tablet0.12USDtablet
Co Clonazepam 0.5 mg Tablet0.12USDtablet
Mylan-Clonazepam 0.5 mg Tablet0.12USDtablet
Novo-Clonazepam 0.5 mg Tablet0.12USDtablet
Phl-Clonazepam 0.5 mg Tablet0.12USDtablet
Phl-Clonazepam-R 0.5 mg Tablet0.12USDtablet
Pms-Clonazepam 0.5 mg Tablet0.12USDtablet
Pms-Clonazepam-R 0.5 mg Tablet0.12USDtablet
Ratio-Clonazepam 0.5 mg Tablet0.12USDtablet
Sandoz Clonazepam 0.5 mg Tablet0.12USDtablet
Pms-Clonazepam 0.25 mg Tablet0.07USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point238-240Kariss, J. and Newmark, H.L.; US. Patents 3,116,203; December 31, 1963; and 3,123,529; March 3, 1964; both assigned to Hoffmann-LaRoche, Inc. Keller, O., Steiger, N. and Sternbach, L.H.; U S . Patents 3,121,114; February 11, 1964; and 3,203890; August 31, 1965; both assigned to Hoffmann-LaRoche, Inc. Focella, A. and Rachlin, A.I.; U.S. Patent 3,335,181; August 8, 1967; assigned to Hoffmann- LaRoche. Inc.
water solubility100 mg/L (at 25 °C)MERCK INDEX (1996)
logP2.41HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility1.06e-02 g/lALOGPS
logP2.76ALOGPS
logP3.15ChemAxon
logS-4.5ALOGPS
pKa (strongest acidic)11.89ChemAxon
pKa (strongest basic)1.86ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count1ChemAxon
polar surface area87.28ChemAxon
rotatable bond count2ChemAxon
refractivity84.02ChemAxon
polarizability29.59ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Kariss, J. and Newmark, H.L.; US. Patents 3,116,203; December 31, 1963; and 3,123,529; March 3, 1964; both assigned to Hoffmann-LaRoche, Inc.
Keller, O., Steiger, N. and Sternbach, L.H.; U S . Patents 3,121,114; February 11, 1964; and 3,203890; August 31, 1965; both assigned to Hoffmann-LaRoche, Inc.
Focella, A. and Rachlin, A.I.; U.S. Patent 3,335,181; August 8, 1967; assigned to Hoffmann- LaRoche. Inc.

General Reference
  1. Dreifuss FE, Penry JK, Rose SW, Kupferberg HJ, Dyken P, Sato S: Serum clonazepam concentrations in children with absence seizures. Neurology. 1975 Mar;25(3):255-8. Pubmed
  2. Robertson MD, Drummer OH: Postmortem drug metabolism by bacteria. J Forensic Sci. 1995 May;40(3):382-6. Pubmed
  3. Rosen GM, Turner MJ 3rd: Synthesis of spin traps specific for hydroxyl radical. J Med Chem. 1988 Feb;31(2):428-32. Pubmed
  4. Rosen GM, Demos HA, Rauckman EJ: Not all aromatic nitro compounds form free radicals. Toxicol Lett. 1984 Aug;22(2):145-52. Pubmed
  5. Earley JV, Fryer RI, Ning RY: Quinazolines and 1,4-benzodiazepines. LXXXIX: Haptens useful in benzodiazepine immunoassay development. J Pharm Sci. 1979 Jul;68(7):845-50. Pubmed
External Links
ResourceLink
KEGG DrugD00280
PubChem Compound2802
PubChem Substance46507677
ChemSpider2700
BindingDB50019213
ChEBI3756
ChEMBLCHEMBL452
Therapeutic Targets DatabaseDAP000259
PharmGKBPA449050
Drug Product Database2242078
RxListhttp://www.rxlist.com/cgi/generic/clonaz.htm
Drugs.comhttp://www.drugs.com/clonazepam.html
WikipediaClonazepam
ATC CodesN03AE01
AHFS Codes
  • 28:12.08
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(74.3 KB)
Interactions
Drug Interactions
Drug
CimetidineCimetidine may increase the effect of the benzodiazepine, clonazepam.
ClozapineIncreased risk of toxicity
FluconazoleFluconazole may increase the effect of the benzodiazepine, clonazepam.
IndinavirThe protease inhibitor, indinavir, may increase the effect of the benzodiazepine, clonazepam.
ItraconazoleItraconazole may increase the effect of the benzodiazepine, clonazepam.
KavaKava may increase the effect of the benzodiazepine, clonazepam.
KetoconazoleKetoconazole may increase the effect of the benzodiazepine, clonazepam.
NelfinavirThe protease inhibitor, nelfinavir, may increase the effect of the benzodiazepine, clonazepam.
OmeprazoleOmeprazole may increase the effect of the benzodiazepine, clonazepam.
RitonavirThe protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, clonazepam.
SaquinavirThe protease inhibitor, saquinavir, may increase the effect of the benzodiazepine, clonazepam.
St. John's WortSt. John's Wort may decrease the effect of the benzodiazepine, clonazepam.
TelithromycinTelithromycin may reduce clearance of Clonazepam. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Clonazepam if Telithromycin is initiated, discontinued or dose changed.
TipranavirTipranavir may decrease the metabolism and clearance of Clonazepam. Consider alternate therapy or monitor for Clonazepam toxic effects if Tipranavir is initiated or dose increased.
TriprolidineThe CNS depressants, Triprolidine and Clonazepam, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
VigabatrinVigabatrin increases Cmax of clonazepam by 30% and decreases Tmax by 45%
VoriconazoleVoriconazole may increase the serum concentration of clonazepam by decreasing its metabolism. Monitor for clonazepam toxicity if voriconazole is initiated or dose increased.
Food Interactions
  • Avoid alcohol.
  • Avoid excessive quantities of coffee or tea (Caffeine).
  • Take without regard to meals.

Targets

1. GABA-A receptor (anion channel)

Kind: protein group

Organism: Human

Pharmacological action: yes

Actions: positive allosteric modulator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-1 P14867 Details
Gamma-aminobutyric acid receptor subunit alpha-2 P47869 Details
Gamma-aminobutyric acid receptor subunit alpha-3 P34903 Details
Gamma-aminobutyric acid receptor subunit alpha-4 P48169 Details
Gamma-aminobutyric acid receptor subunit alpha-5 P31644 Details
Gamma-aminobutyric acid receptor subunit alpha-6 Q16445 Details
Gamma-aminobutyric acid receptor subunit beta-1 P18505 Details
Gamma-aminobutyric acid receptor subunit beta-2 P47870 Details
Gamma-aminobutyric acid receptor subunit beta-3 P28472 Details
Gamma-aminobutyric acid receptor subunit delta O14764 Details
Gamma-aminobutyric acid receptor subunit epsilon P78334 Details
Gamma-aminobutyric acid receptor subunit gamma-1 Q8N1C3 Details
Gamma-aminobutyric acid receptor subunit gamma-2 P18507 Details
Gamma-aminobutyric acid receptor subunit gamma-3 Q99928 Details
Gamma-aminobutyric acid receptor subunit pi O00591 Details
Gamma-aminobutyric acid receptor subunit theta Q9UN88 Details

References:

  1. Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. Pubmed
  2. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. Epub 2008 Mar 31. Pubmed

2. Translocator protein

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Translocator protein P30536 Details

References:

  1. Carmel I, Fares FA, Leschiner S, Scherubl H, Weisinger G, Gavish M: Peripheral-type benzodiazepine receptors in the regulation of proliferation of MCF-7 human breast carcinoma cell line. Biochem Pharmacol. 1999 Jul 15;58(2):273-8. Pubmed
  2. Bono F, Lamarche I, Prabonnaud V, Le Fur G, Herbert JM: Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities. Biochem Biophys Res Commun. 1999 Nov 19;265(2):457-61. Pubmed
  3. Bolger GT, Abraham S, Oz N, Weissman BA: Interactions between peripheral-type benzodiazepine receptor ligands and an activator of voltage-operated calcium channels. Can J Physiol Pharmacol. 1990 Jan;68(1):40-5. Pubmed
  4. Marano G, Massotti M, Spagnolo A, Carpi A: Enhancement of pharmacologically induced bronchoconstriction by Ro 5-4864. Eur J Pharmacol. 1990 Apr 10;179(1-2):237-40. Pubmed
  5. Awad M, Gavish M: Solubilization of peripheral-type benzodiazepine binding sites from cat cerebral cortex. J Neurochem. 1989 Jun;52(6):1880-5. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

2. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Tassaneeyakul W, Birkett DJ, Miners JO: Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents. Xenobiotica. 1998 Mar;28(3):293-301. Pubmed

3. Arylamine N-acetyltransferase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Arylamine N-acetyltransferase 2 P11245 Details

References:

  1. Olivera M, Martinez C, Gervasini G, Carrillo JA, Ramos S, Benitez J, Garcia-Martin E, Agundez JA: Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam. Drug Metab Lett. 2007 Jan;1(1):3-5. Pubmed
  2. Miller ME, Garland WA, Min BH, Ludwick BT, Ballard RH, Levy RH: Clonazepam acetylation in fast and slow acetylators. Clin Pharmacol Ther. 1981 Sep;30(3):343-7. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: no

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Pacifici GM, Viani A, Rizzo G, Carrai M, Rane A: Plasma protein binding of clonazepam in hepatic and renal insufficiency and after hemodialysis. Ther Drug Monit. 1987 Dec;9(4):369-73. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on April 08, 2014 11:18