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Identification
NameClobazam
Accession NumberDB00349  (APRD00307)
TypeSmall Molecule
GroupsApproved, Illicit
Description

Clobazam belongs to the 1,5-benzodiazepine class of drugs and is expected to have a better side-effect profile compared to older 1,4-benzodiazepines. It has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984. The oral preparation was FDA approved on October 21, 2011. An oral suspension is expected to be available in 2013.

Structure
Thumb
Synonyms
SynonymLanguageCode
1-phenyl-5-methyl-8-chloro-1,2,4,5-tetrahydro-2,4-dioxo-3H-1,5-benzodiazepineNot AvailableNot Available
7-Chloro-1-methyl-5-phenyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dioneNot AvailableIUPAC
ClobazamNot AvailableBAN, DCF, DCIT, USAN, BP 2011, Ph. Eur. 7
ClobazamumLatinPh. Eur. 7
SaltsNot Available
Brand names
NameCompany
AedonSanofi-Aventis
CastiliumSanofi-Aventis
ClobamSquare
ClobamaxSherfarma
FrisiumSanofi-Aventis
GrifoclobamChile
MystanDainippon Sumitomo
NoiafrenSanofi Aventis
OnfiLundbeck
SederlonaNot Available
UrbanilSanofi-Aventis
UrbanolSanofi-Aventis
UrbanylSanofi-Aventis
VeniumHudson
Brand mixturesNot Available
Categories
CAS number22316-47-8
WeightAverage: 300.74
Monoisotopic: 300.066555377
Chemical FormulaC16H13ClN2O2
InChI KeyCXOXHMZGEKVPMT-UHFFFAOYSA-N
InChI
InChI=1S/C16H13ClN2O2/c1-18-13-8-7-11(17)9-14(13)19(16(21)10-15(18)20)12-5-3-2-4-6-12/h2-9H,10H2,1H3
IUPAC Name
7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-dione
SMILES
CN1C2=C(C=C(Cl)C=C2)N(C2=CC=CC=C2)C(=O)CC1=O
Mass Specshow(11.4 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzodiazepines
SubclassNot Available
Direct parentBenzodiazepines
Alternative parentsChlorobenzenes; Aryl Chlorides; Tertiary Carboxylic Acid Amides; Tertiary Amines; Polyamines; Carboxylic Acids; Organochlorides
Substituentschlorobenzene; benzene; aryl halide; aryl chloride; tertiary carboxylic acid amide; tertiary amine; carboxamide group; polyamine; carboxylic acid; carboxylic acid derivative; organohalogen; organochloride; amine; organonitrogen compound
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
IndicationFor treatment and management of epilepsy and seizures associated with Lennox-Gastaut syndrome, a difficult-to-treat form of childhood epilepsy.
PharmacodynamicsSimilar to other benzodiazepines, clobazam binds to the interface of the α and γ2-subunit of the GABA-A receptor. However, it is considered a partial agonist to GABA-A receptors which sets clobazam apart from 1,4-benzodiazepines which are full agonist. The significance of this difference is that one may experience less sedation with clobazam than with other benzodiazepines. Unlike the endogenous GABA ligand, clobazam binds allosterically to the GABA receptor to increase the frequency of the chloride channel opening and membrane permeability to chloride ions. Pharmacodynamic tolerance has been demonstrated in animal models.
Mechanism of actionClobazam binds at distinct binding sites associated with the chloride ionopore at the post-synaptic GABA receptor. These GABA receptors are in various locations in the CNS (limbic, reticular formation) and clobazam increases the duration of time for which the chloride ionopore is open. As a result, hyper polarization and stabilization of the membrane occur as the post-synaptic inhibitory effect of GABA is enhanced.
AbsorptionAfter oral administration of clobazam, it is almost completely absorbed (87% of dose). Bioavailability relative to solution was almost at 100%. Food does not affect absorption. Tmax = 1-3 hours.
Volume of distribution

Vdss = 100 L. This high volume of distribution suggests extensive distribution to body tissues.

Protein bindingClobazam is the primary circulating entity in the serum and is highly protein-bound (80-90%).
Metabolism

Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation. Clobazam has two major metabolites: N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, the former of which is active. Norclobazam is one-fourth the potency of clobazam. The main enzyme that facilitates the process of N-demethylation is CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6. Norclobazam itself is also metabolized via hydroxylation, primarily by CYP2C19. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19. A factor in determining extent of metabolism is the genetic profile of the individual patient as CYP2C19 is a polymorphic enzyme.

SubstrateEnzymesProduct
Clobazam
norclobazamDetails
Clobazam
Not Available
4'-hydroxyclobazamDetails
Route of eliminationClobazam is eliminated via the urine (~94%) as metabolites.
Half lifeThe mean elimination half life of an oral dose of clobazam 40 mg is 32 hours. It's main metabolite, norclobazam, as a half life of 57 hours. The half life in adult patients with epilepsy are higher than those that are healthy.
Clearance

Median estimated clearance = 2.49 L/h

ToxicityThe most common adverse effects include somnolence, pyrexia, upper respiratory tract infection, and lethargy.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
rs4244285 CYP2C19*2G > A/CClobazem is metabolized into N-desmethylclobazem (NCLB) mostly by CYP3A4. NCLB is primarily metabolized by 2C19. Those with one 2C19*2 allele mutation (1*/2*) are intermediate metabolizers of NCLB. Those with two (2*/2*) mutations will metabolize NCLB poorly in comparisone to extensive metabolizers (1*/1*). Levels of NCLB can be five times higher in poor metabolizers, and two times higher in intermediate metabolizers as compared to individuals who are extensive metabolizers. The safety and efficacy of clobazem may be affected by polymorphic expression of CYP2C19*2.15483195
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.99
Blood Brain Barrier + 0.9904
Caco-2 permeable + 0.7487
P-glycoprotein substrate Non-substrate 0.5733
P-glycoprotein inhibitor I Non-inhibitor 0.5462
P-glycoprotein inhibitor II Non-inhibitor 0.9204
Renal organic cation transporter Non-inhibitor 0.7373
CYP450 2C9 substrate Non-substrate 0.7058
CYP450 2D6 substrate Non-substrate 0.8607
CYP450 3A4 substrate Substrate 0.6871
CYP450 1A2 substrate Non-inhibitor 0.6829
CYP450 2C9 substrate Non-inhibitor 0.5296
CYP450 2D6 substrate Non-inhibitor 0.8908
CYP450 2C19 substrate Non-inhibitor 0.5791
CYP450 3A4 substrate Inhibitor 0.7008
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5308
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.7846
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 1.7313 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9896
hERG inhibition (predictor II) Non-inhibitor 0.8651
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
SuspensionOral2.5 mg/mL
TabletOral5 mg, 10 mg, 20 mg
Prices
Unit descriptionCostUnit
Apo-Clobazam 10 mg Tablet0.23USDtablet
Novo-Clobazam 10 mg Tablet0.23USDtablet
Pms-Clobazam 10 mg Tablet0.23USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point180-182Hauptmann, K.H., Weber, K.-H., Zeile, K., Danneberg, P. and Giesemann, R.; South African Patent 68/0803; February 7,1968; assigned to Boehringer lngelheim GmbH, Germany.
water solubility188 mg/LNot Available
logP2.12HENCZI,M ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.164ALOGPS
logP2.14ALOGPS
logP2.55ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)4.07ChemAxon
pKa (Strongest Basic)-6.7ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area40.62 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity80.3 m3·mol-1ChemAxon
Polarizability30.07 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Hauptmann, K.H., Weber, K.-H., Zeile, K., Danneberg, P. and Giesemann, R.; South African
Patent 68/0803; February 7,1968; assigned to Boehringer lngelheim GmbH, Germany.

General Reference
  1. Freche C: [Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations] Sem Hop Ther. 1975 Apr;51(4):261-3. Pubmed
  2. : Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group. Epilepsia. 1991 May-Jun;32(3):407-16. Pubmed
  3. Wildin JD, Pleuvry BJ, Mawer GE, Onon T, Millington L: Respiratory and sedative effects of clobazam and clonazepam in volunteers. Br J Clin Pharmacol. 1990 Feb;29(2):169-77. Pubmed
  4. Kilpatrick C, Bury R, Fullinfaw R, Moulds R: Clobazam in the treatment of epilepsy. Clin Exp Neurol. 1987;23:139-44. Pubmed
  5. Giarratano M, Standley K, Benbadis SR: Clobazam for treatment of epilepsy. Expert Opin Pharmacother. 2012 Feb;13(2):227-33. doi: 10.1517/14656566.2012.647686. Epub 2012 Jan 13. Pubmed
  6. Yang LP, Scott LJ: Clobazam : in patients with Lennox-Gastaut syndrome. CNS Drugs. 2012 Nov;26(11):983-91. doi: 10.1007/s40263-012-0007-0. Pubmed
  7. Walzer M, Bekersky I, Blum RA, Tolbert D: Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes. Pharmacotherapy. 2012 Apr;32(4):340-53. doi: 10.1002/j.1875-9114.2012.01028.×. Epub 2012 Mar 15. Pubmed
External Links
ResourceLink
KEGG DrugD01253
PubChem Compound2789
PubChem Substance46506115
ChemSpider2687
ChEBI31413
ChEMBLCHEMBL70418
Therapeutic Targets DatabaseDAP000672
PharmGKBPA10888
Drug Product Database2247230
RxListhttp://www.rxlist.com/onfi-drug.htm
Drugs.comhttp://www.drugs.com/cdi/clobazam.html
WikipediaClobazam
ATC CodesN05BA09
AHFS Codes
  • 28:24.08
PDB EntriesNot Available
FDA labelshow(595 KB)
MSDSshow(57.5 KB)
Interactions
Drug Interactions
Drug
AxitinibClobazam decreases levels by affecting CYP3A4 metabolism. Consider alternate therapy.
ClozapineIncreased risk of toxicity
KavaKava may increase the effect of the benzodiazepine, clobazam.
KetoconazoleClobazam may increase levels by affecting CYP2C19 metabolism. Interaction is significant so monitor closely. Dose adjustment may be necessary.
MidazolamClobazam decrease the Cmax and AUC of midazolam by approximately 25% of both and increases the Cmax and AUC of its metabolite. Dose adjustment is not necessary.
RotigotineConcomitant therapy may potentiate adverse CNS effects such as increased sedation or respiratory depression. Monitor therapy closely.
TelithromycinTelithromycin may reduce clearance of Clobazam. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Clobazam if Telithromycin is initiated, discontinued or dose changed.
TiclopidineTiclopidine may decrease the metabolism and clearance of Clobazam. Consider alternate therapy or monitor for adverse/toxic effects of Clobazam if Ticlopidine is initiated, discontinued or dose changed.
TipranavirTipranavir may decrease the metabolism and clearance of Clobazam. Consider alternate therapy or monitor for Clobazam toxic effects if Tipranavir is initiated or dose increased.
TriprolidineThe CNS depressants, Triprolidine and Clobazam, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
VoriconazoleVoriconazole may increase the serum concentration of clobazam by decreasing its metabolism. Monitor for clobazam toxicity if voriconazole is initiated or dose increased.
Food Interactions
  • Alcohol increases clobazam absorption by 50%.
  • 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

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. FDA label

2. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 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

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 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

4. Cytochrome P450 2C18

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C18 P33260 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

Transporters

1. Sodium- and chloride-dependent GABA transporter 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: Other

Components

Name UniProt ID Details
Sodium- and chloride-dependent GABA transporter 1 P30531 Details

References:

  1. Giarratano M, Standley K, Benbadis SR: Clobazam for treatment of epilepsy. Expert Opin Pharmacother. 2012 Feb;13(2):227-33. doi: 10.1517/14656566.2012.647686. Epub 2012 Jan 13. Pubmed

2. Sodium- and chloride-dependent GABA transporter 3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: Other

Components

Name UniProt ID Details
Sodium- and chloride-dependent GABA transporter 3 P48066 Details

References:

  1. Giarratano M, Standley K, Benbadis SR: Clobazam for treatment of epilepsy. Expert Opin Pharmacother. 2012 Feb;13(2):227-33. doi: 10.1517/14656566.2012.647686. Epub 2012 Jan 13. Pubmed

3. 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. FDA label

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Drug created on June 13, 2005 07:24 / Updated on April 07, 2014 15:06