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药品详细

Clobazam(氯巴占)

化学结构式图
中文名
氯巴占
英文名
Clobazam
分子式
C16H13ClN2O2
化学名
7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-dione
分子量
Average: 300.74
Monoisotopic: 300.066555377
CAS号
22316-47-8
ATC分类
N05B 未知
药物类型
small molecule
阶段
illicit, approved
商品名
同义名
基本介绍

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.

生产厂家
    封装厂家
    参考
    Synthesis Reference Not Available
    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
    剂型
    规格
    化合物类型
    Type small molecule
    Classes
    • Benzene and Derivatives
    • Halobenzenes
    • Lactams
    • Anilines
    Substructures
    • Amino Ketones
    • Benzene and Derivatives
    • Aliphatic and Aryl Amines
    • Aryl Halides
    • Halobenzenes
    • Heterocyclic compounds
    • Aromatic compounds
    • Carboxamides and Derivatives
    • Lactams
    • Anilines
    适应症
    药理
    Indication For treatment and management of epilepsy and seizures associated with Lennox-Gastaut syndrome, a difficult-to-treat form of childhood epilepsy.
    Pharmacodynamics Similar 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 action Clobazam 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.
    Absorption After 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 binding Clobazam 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.

    Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

    Substrate Enzymes Product
    Clobazam
    		norclobazam Details
    Clobazam
      		4'-hydroxyclobazam Details
      Route of elimination Clobazam is eliminated via the urine (~94%) as metabolites.
      Half life The 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
      Toxicity The most common adverse effects include somnolence, pyrexia, upper respiratory tract infection, and lethargy.
      Affected organisms
      • Humans and other mammals
      Pathways Not Available
      理化性质
      Properties
      State solid
      Experimental Properties
      Property Value Source
      water solubility 188 mg/L Not Available
      logP 2.12 HENCZI,M ET AL. (1995)
      Predicted Properties
      Property Value Source
      water solubility 1.64e-01 g/l ALOGPS
      logP 2.14 ALOGPS
      logP 2.55 ChemAxon
      logS -3.3 ALOGPS
      pKa (strongest acidic) 4.07 ChemAxon
      pKa (strongest basic) -6.7 ChemAxon
      physiological charge -1 ChemAxon
      hydrogen acceptor count 2 ChemAxon
      hydrogen donor count 0 ChemAxon
      polar surface area 40.62 ChemAxon
      rotatable bond count 1 ChemAxon
      refractivity 80.3 ChemAxon
      polarizability 30.07 ChemAxon
      药物相互作用
      Drug Interaction
      Axitinib Clobazam decreases levels by affecting CYP3A4 metabolism. Consider alternate therapy.
      Clozapine Increased risk of toxicity
      Kava Kava may increase the effect of the benzodiazepine, clobazam.
      Ketoconazole Clobazam may increase levels by affecting CYP2C19 metabolism. Interaction is significant so monitor closely. Dose adjustment may be necessary.
      Midazolam Clobazam 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.
      Rotigotine Concomitant therapy may potentiate adverse CNS effects such as increased sedation or respiratory depression. Monitor therapy closely.
      Telithromycin Telithromycin 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.
      Ticlopidine Ticlopidine 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.
      Tipranavir Tipranavir may decrease the metabolism and clearance of Clobazam. Consider alternate therapy or monitor for Clobazam toxic effects if Tipranavir is initiated or dose increased.
      Triprolidine The CNS depressants, Triprolidine and Clobazam, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
      Voriconazole Voriconazole may increase the serum concentration of clobazam by decreasing its metabolism. Monitor for clobazam toxicity if voriconazole is initiated or dose increased.
      食物相互作用
      • Alcohol increases clobazam absorption by 50%.
      • Take without regard to meals.

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