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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 KeyInChIKey=CXOXHMZGEKVPMT-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
    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 solubility1.64e-01 g/lALOGPS
    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 area40.62ChemAxon
    rotatable bond count1ChemAxon
    refractivity80.3ChemAxon
    polarizability30.07ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    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.

    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

    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

    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

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