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Identification
NameFlumazenil
Accession NumberDB01205  (APRD00974)
Typesmall molecule
Groupsapproved
Description

Fumazenil is an imidazobenzodiazepine derivative and a potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system.

Structure
Thumb
Synonyms
SynonymLanguageCode
AnexateNot AvailableNot Available
FlumazeniloSpanishINN
FlumazenilumLatinINN
FlumazepilNot AvailableNot Available
LanexatNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AnexateHoffmann-La Roche
LanexatNot Available
MaziconNot Available
RomaziconNot Available
Brand mixturesNot Available
Categories
CAS number78755-81-4
WeightAverage: 303.2884
Monoisotopic: 303.101919534
Chemical FormulaC15H14FN3O3
InChI KeyOFBIFZUFASYYRE-UHFFFAOYSA-N
InChI
InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3
IUPAC Name
ethyl 12-fluoro-8-methyl-9-oxo-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,11,13-pentaene-5-carboxylate
SMILES
CCOC(=O)C1=C2CN(C)C(=O)C3=C(C=CC(F)=C3)N2C=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassHalobenzenes
Direct parentFluorobenzenes
Alternative parentsCarbonylimidazoles; Aryl Fluorides; N-substituted Imidazoles; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acid Esters; Carboxylic Acids; Dialkyl Ethers; Polyamines; Enolates; Organofluorides
Substituentsaryl fluoride; n-substituted imidazole; aryl halide; tertiary carboxylic acid amide; azole; imidazole; carboxamide group; tertiary amine; carboxylic acid ester; carboxylic acid derivative; polyamine; enolate; ether; dialkyl ether; carboxylic acid; organofluoride; organohalogen; amine; organonitrogen compound
Classification descriptionThis compound belongs to the fluorobenzenes. These are compounds containing one or more fluorine atoms attached to a benzene ring.
Pharmacology
IndicationFor the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures.
PharmacodynamicsFlumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
Mechanism of actionFlumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
AbsorptionNot Available
Volume of distribution
  • 0.9 to 1.1 L/kg
Protein bindingProtein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.
Metabolism

Hepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.

Route of eliminationFlumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.
Half lifeInitial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).
Clearance
  • 1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]
ToxicityIn clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.
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 + 0.9937
Blood Brain Barrier + 0.9382
Caco-2 permeable + 0.5355
P-glycoprotein substrate Substrate 0.6137
P-glycoprotein inhibitor I Non-inhibitor 0.8502
P-glycoprotein inhibitor II Non-inhibitor 0.8382
Renal organic cation transporter Non-inhibitor 0.7508
CYP450 2C9 substrate Non-substrate 0.8402
CYP450 2D6 substrate Non-substrate 0.8404
CYP450 3A4 substrate Substrate 0.5764
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Inhibitor 0.8995
CYP450 3A4 substrate Non-inhibitor 0.866
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5863
Ames test Non AMES toxic 0.6348
Carcinogenicity Non-carcinogens 0.8872
Biodegradation Not ready biodegradable 0.9928
Rat acute toxicity 1.8903 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.987
hERG inhibition (predictor II) Non-inhibitor 0.6394
Pharmacoeconomics
Manufacturers
  • Akorn strides llc
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Bedford laboratories
  • Claris lifesciences ltd
  • Hikma farmaceutica (portugal) sa
  • Sandoz canada inc
  • Teva parenteral medicines inc
  • Hoffmann la roche inc
Packagers
Dosage forms
FormRouteStrength
SolutionIntravenous
Prices
Unit descriptionCostUnit
Romazicon 0.1 mg/ml vial25.14USDml
Flumazenil 0.1 mg/ml vial1.63USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point201-203 °CPhysProp
water solubility128 mg/LNot Available
logP1.00MFG DATA SHEET
Predicted Properties
PropertyValueSource
water solubility1.04e+00 g/lALOGPS
logP1.54ALOGPS
logP0.33ChemAxon
logS-2.5ALOGPS
pKa (strongest basic)3.27ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count0ChemAxon
polar surface area64.43ChemAxon
rotatable bond count3ChemAxon
refractivity87.93ChemAxon
polarizability29.97ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Ngo AS, Anthony CR, Samuel M, Wong E, Ponampalam R: Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation. 2007 Jul;74(1):27-37. Epub 2007 Feb 15. Pubmed
  2. Olkkola KT, Ahonen J: Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;(182):335-60. Pubmed
  3. Maeda S, Miyawaki T, Higuchi H, Shimada M: Effect of flumazenil on disturbance of equilibrium function induced by midazolam. Anesth Prog. 2008 Fall;55(3):73-7. Pubmed
External Links
ResourceLink
KEGG DrugD00697
KEGG CompoundC07825
PubChem Compound3373
PubChem Substance46507438
ChemSpider3256
BindingDB26263
ChEBI5103
ChEMBLCHEMBL407
Therapeutic Targets DatabaseDAP000685
PharmGKBPA449659
Drug Product Database2249561
RxListhttp://www.rxlist.com/cgi/generic3/flumazenil.htm
Drugs.comhttp://www.drugs.com/cdi/flumazenil.html
WikipediaFlumazenil
ATC CodesV03AB25
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelshow(244 KB)
MSDSshow(51.1 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Gamma-aminobutyric acid receptor subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-1 P14867 Details

References:

  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  2. Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. Pubmed
  3. Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. Pubmed

2. Gamma-aminobutyric acid receptor subunit gamma-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit gamma-2 P18507 Details

References:

  1. Padgett CL, Lummis SC: The F-loop of the GABA A receptor gamma2 subunit contributes to benzodiazepine modulation. J Biol Chem. 2008 Feb 1;283(5):2702-8. Epub 2007 Oct 31. Pubmed
  2. Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. Pubmed
  3. Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. Pubmed

3. Gamma-aminobutyric acid receptor subunit alpha-5

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-5 P31644 Details

References:

  1. Clement Y, Le Guisquet AM, Venault P, Chapouthier G, Belzung C: Pharmacological alterations of anxious behaviour in mice depending on both strain and the behavioural situation. PLoS One. 2009 Nov 11;4(11):e7745. doi: 10.1371/journal.pone.0007745. Pubmed

4. 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. ChEMBL Compound Report Card (Accessed December 2013)

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13