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Identification
NameClorazepate
Accession NumberDB00628  (APRD00881)
Typesmall molecule
Groupsapproved, illicit
Description

A water-soluble benzodiazepine derivative effective in the treatment of anxiety. It has also muscle relaxant and anticonvulsant actions. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
Clorazepic acidNot AvailableBAN
Salts
Name/CAS Structure Properties
Clorazepate dipotassium
Thumb Not applicable DBSALT000953
Brand names
NameCompany
AnksenSanovel
CalnerMedipharm
CloranxenTeva
Clorazepatumsanofi-aventis
ClozeneWeidar
DipotAsian
FluliumPharmasant
Gen-xeneAlra
JustumSandoz
ManotranMarch
MedipaxTecnifar
MendonAbbott Japan
PolizepPolipharm
TencilanFinadiet
TrancapT P Drug
Transenesanofi-aventis
Tranxensanofi-aventis
Tranxènesanofi-aventis
TranxeneLundbeck
Tranxene T-TabLundbeck
Tranxilenesanofi-aventis
Tranxiliumsanofi-aventis
Zetran-5Masa Lab
Brand mixturesNot Available
CategoriesNot Available
CAS number23887-31-2
WeightAverage: 314.723
Monoisotopic: 314.045819935
Chemical FormulaC16H11ClN2O3
InChI KeyInChIKey=XDDJGVMJFWAHJX-UHFFFAOYSA-N
InChI
InChI=1S/C16H11ClN2O3/c17-10-6-7-12-11(8-10)13(9-4-2-1-3-5-9)19-14(16(21)22)15(20)18-12/h1-8,14H,(H,18,20)(H,21,22)
IUPAC Name
7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-carboxylic acid
SMILES
OC(=O)C1N=C(C2=CC=CC=C2)C2=C(NC1=O)C=CC(Cl)=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzodiazepines
SubclassNot Available
Direct parentBenzodiazepines
Alternative parentsChlorobenzenes; Aryl Chlorides; Secondary Carboxylic Acid Amides; Enolates; Carboxylic Acids; Polyamines; Organochlorides; Alcohols and Polyols
Substituentschlorobenzene; aryl chloride; aryl halide; benzene; carboxamide group; secondary carboxylic acid amide; polyamine; carboxylic acid; carboxylic acid derivative; enolate; organochloride; organohalogen; alcohol; 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 the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Also used as adjunctive therapy in the management of partial seizures and for the symptomatic relief of acute alcohol withdrawal.
PharmacodynamicsClorazepate is a member of the group of drugs called benzodiazepines. Pharmacologically, clorazepate has the characteristics of the benzodiazepines. It has depressant effects on the central nervous system. The primary metabolite, nordiazepam, quickly appears in the blood stream. Studies in healthy men have shown that clorazenate has depressant effects on the central nervous system. Since orally administered clorazepate dipotassium is rapidly decarboxylated to form nordiazepam, there is essentially no circulating parent drug.
Mechanism of actionBenzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
AbsorptionRapidly absorbed following oral administration (bioavailability is 91%).
Volume of distributionNot Available
Protein bindingThe protein binding of nordiazepam in plasma is high (97-98%).
Metabolism

The drug is metabolized in the liver and excreted primarily in the urine. The primary metabolite, nordiazepam, is further metabolized by hydroxylation. The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p-hydroxynordiazepam and nordiazepam are also found in the urine.

SubstrateEnzymesProduct
Clorazepate
    OxazepamDetails
    Clorazepate
      3-hydroxynordiazepamDetails
      Clorazepate
      NordiazepamDetails
      Clorazepate
        p-HydroxynordiazepamDetails
        Route of eliminationThe drug is metabolized in the liver and excreted primarily in the urine.
        Half lifeThe serum half-life is about 2 days. Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about 40 to 50 hours.
        ClearanceNot Available
        ToxicityOral LD50 in rats is 1320 mg/kg. In monkeys, oral LD50 exceed 1600 mg/kg. Symptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time.
        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 + 0.9285
        Blood Brain Barrier + 0.8373
        Caco-2 permeable + 0.5909
        P-glycoprotein substrate Non-substrate 0.5597
        P-glycoprotein inhibitor I Non-inhibitor 0.9328
        P-glycoprotein inhibitor II Non-inhibitor 0.9386
        Renal organic cation transporter Non-inhibitor 0.9049
        CYP450 2C9 substrate Non-substrate 0.7365
        CYP450 2D6 substrate Non-substrate 0.8745
        CYP450 3A4 substrate Non-substrate 0.5798
        CYP450 1A2 substrate Inhibitor 0.7086
        CYP450 2C9 substrate Non-inhibitor 0.756
        CYP450 2D6 substrate Non-inhibitor 0.819
        CYP450 2C19 substrate Non-inhibitor 0.7451
        CYP450 3A4 substrate Non-inhibitor 0.8333
        CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8165
        Ames test Non AMES toxic 0.8311
        Carcinogenicity Non-carcinogens 0.659
        Biodegradation Not ready biodegradable 1.0
        Rat acute toxicity 1.9282 LD50, mol/kg Not applicable
        hERG inhibition (predictor I) Weak inhibitor 0.9987
        hERG inhibition (predictor II) Non-inhibitor 0.9207
        Pharmacoeconomics
        Manufacturers
        • Able laboratories inc
        • American therapeutics inc
        • Clonmel healthcare ltd
        • Gd searle llc
        • Mylan pharmaceuticals inc
        • Purepac pharmaceutical co
        • Quantum pharmics ltd
        • Sandoz inc
        • Usl pharma inc
        • Warner chilcott div warner lambert co
        • Watson laboratories inc
        • Lundbeck inc
        • Lederle laboratories div american cyanamid co
        • Ranbaxy laboratories ltd
        • Taro pharmaceuticals usa inc
        • Alra laboratories inc
        Packagers
        Dosage forms
        FormRouteStrength
        CapsuleOral
        Prices
        Unit descriptionCostUnit
        Tranxene t-tablet 15 mg5.41USDtablet
        Tranxene-T 15 mg tablet5.08USDtablet
        Tranxene t-tablet 7.5 mg3.99USDtablet
        Tranxene-T 7.5 mg tablet3.6USDtablet
        Tranxene t-tablet 3.75 mg3.21USDtablet
        Tranxene-T 3.75 mg tablet3.04USDtablet
        Clorazepate 15 mg tablet2.17USDtablet
        Clorazepate Dipotassium 15 mg tablet1.27USDtablet
        Clorazepate Dipotassium 7.5 mg tablet0.93USDtablet
        Clorazepate 7.5 mg tablet0.79USDtablet
        Clorazepate Dipotassium 3.75 mg tablet0.76USDtablet
        Clorazepate 3.75 mg tablet0.73USDtablet
        Apo-Clorazepate 15 mg Capsule0.4USDcapsule
        Apo-Clorazepate 7.5 mg Capsule0.2USDcapsule
        Apo-Clorazepate 3.75 mg Capsule0.15USDcapsule
        DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
        PatentsNot Available
        Properties
        Statesolid
        Experimental Properties
        PropertyValueSource
        water solubilityVery solubleNot Available
        logP3Not Available
        Predicted Properties
        PropertyValueSource
        water solubility2.48e-02 g/lALOGPS
        logP2.68ALOGPS
        logP3.21ChemAxon
        logS-4.1ALOGPS
        pKa (strongest acidic)3.32ChemAxon
        pKa (strongest basic)-0.64ChemAxon
        physiological charge-1ChemAxon
        hydrogen acceptor count4ChemAxon
        hydrogen donor count2ChemAxon
        polar surface area78.76ChemAxon
        rotatable bond count2ChemAxon
        refractivity82.68ChemAxon
        polarizability30.63ChemAxon
        number of rings3ChemAxon
        bioavailability1ChemAxon
        rule of fiveYesChemAxon
        Ghose filterYesChemAxon
        Veber's ruleNoChemAxon
        MDDR-like ruleNoChemAxon
        Spectra
        SpectraNot Available
        References
        Synthesis Reference

        Schmitt, J.; U.S. Patent 3,516,988; June 23, 1970.

        General Reference
        1. : Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines. Br Med J. 1980 Mar 29;280(6218):910-2. Pubmed
        2. McElhatton PR: The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol. 1994 Nov-Dec;8(6):461-75. Pubmed
        External Links
        ResourceLink
        KEGG DrugD00694
        PubChem Compound2809
        PubChem Substance46506595
        ChemSpider2707
        ChEBI3761
        ChEMBLCHEMBL1213252
        Therapeutic Targets DatabaseDAP000240
        PharmGKBPA164749297
        Drug Product Database628190
        RxListhttp://www.rxlist.com/cgi/generic2/clorazepate.htm
        Drugs.comhttp://www.drugs.com/cdi/clorazepate.html
        WikipediaClorazepate
        ATC CodesN05BA05
        AHFS Codes
        • 28:24.08
        PDB EntriesNot Available
        FDA labelNot Available
        MSDSNot Available
        Interactions
        Drug Interactions
        Drug
        AmprenavirAmprenavir may increase the effect and toxicity of the benzodiazepine, clorazepate.
        CimetidineCimetidine may increase the effect of the benzodiazepine, clorazepate.
        ClozapineIncreased risk of toxicity
        EthotoinEthotoin may increase the metabolism of clorazepate via CYP3A4.
        FluconazoleFluconazole may increase the effect of the benzodiazepine, clorazepate.
        FosamprenavirFosamprenavir may increase the effect and toxicity of the benzodiazepine, clorazepate.
        FosphenytoinFosphenytoin may increase the metabolism of clorazepate via CYP3A4.
        IndinavirThe protease inhibitor, indinavir, may increase the effect of the benzodiazepine, clorazepate.
        ItraconazoleItraconazole may increase the effect of the benzodiazepine, clorazepate.
        KavaKava may increase the effect of the benzodiazepine, clorazepate.
        KetoconazoleKetoconazole may increase the effect of the benzodiazepine, clorazepate.
        MephenytoinMephenytoin may increase the metabolism of clorazepate via CYP3A4.
        NelfinavirThe protease inhibitor, nelfinavir, may increase the effect of the benzodiazepine, clorazepate.
        OmeprazoleOmeprazole may increase the effect of the benzodiazepine, clorazepate.
        PhenytoinPhenytoin may increase the metabolism of clorazepate via CYP3A4.
        RitonavirThe protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, clorazepate.
        SaquinavirThe protease inhibitor, saquinavir, may increase the effect of the benzodiazepine, clorazepate.
        TelithromycinTelithromycin may reduce clearance of Clorazepate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Clorazepate if Telithromycin is initiated, discontinued or dose changed.
        TipranavirTipranavir may decrease the metabolism and clearance of Clorazepate. Consider alternate therapy or monitor for Clorazepate toxic effects if Tipranavir is initiated or dose increased.
        TriprolidineThe CNS depressants, Triprolidine and Clorazepate, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
        VoriconazoleVoriconazole may increase the serum concentration of clorazepate by decreasing its metabolism. Monitor for clorazepate toxicity if voriconazole is initiated or dose increased.
        Food Interactions
        • Avoid alcohol.
        • 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

        2. Translocator protein

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: agonist

        Components

        Name UniProt ID Details
        Translocator protein P30536 Details

        References:

        1. Park CH, Carboni E, Wood PL, Gee KW: Characterization of peripheral benzodiazepine type sites in a cultured murine BV-2 microglial cell line. Glia. 1996 Jan;16(1):65-70. 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. Dresser GK, Spence JD, Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000 Jan;38(1):41-57. Pubmed
        2. Sachs B, Erdmann S, Al-Masaoudi T, Merk HF: In vitro drug allergy detection system incorporating human liver microsomes in chlorazepate-induced skin rash: drug-specific proliferation associated with interleukin-5 secretion. Br J Dermatol. 2001 Feb;144(2):316-20. Pubmed

        Comments
        Drug created on June 13, 2005 07:24 / Updated on April 08, 2014 11:29