Identification

Name
Flunitrazepam
Accession Number
DB01544
Description

Flunitrazepam is a benzodiazepine with pharmacologic actions similar to those of diazepam that can cause anterograde amnesia. Some reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. The United States Government has banned the importation of this drug.

Type
Small Molecule
Groups
Approved, Illicit
Structure
Thumb
Weight
Average: 313.2832
Monoisotopic: 313.08626947
Chemical Formula
C16H12FN3O3
Synonyms
  • Flunitrazepamum
External IDs
  • RO 5-4200
  • RO-5-4200
  • RO-54200

Pharmacology

Indication

For short-term treatment of severe insomnias, that are not responsive to other hypnotics.

Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More
Pharmacodynamics

Flunitrazepam is a powerful hypnotic drug that is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes used as a date rape drug. In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug. It has however been approved in the United Kingdom and other countries.

Mechanism of action

Benzodiazepines 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.

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
AGABA(A) Receptor Benzodiazepine Binding Site
ligand
Humans
Absorption

50% (suppository) and 64-77% (oral)

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic.

Route of elimination
Not Available
Half-life

18-26 hours

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

Symptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirThe metabolism of Abacavir can be decreased when combined with Flunitrazepam.
AbametapirThe serum concentration of Flunitrazepam can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Flunitrazepam can be increased when combined with Abatacept.
AbirateroneThe metabolism of Flunitrazepam can be decreased when combined with Abiraterone.
AcemetacinThe metabolism of Acemetacin can be decreased when combined with Flunitrazepam.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Flunitrazepam.
AcetaminophenFlunitrazepam may increase the hepatotoxic activities of Acetaminophen.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Flunitrazepam.
AcetohexamideThe metabolism of Flunitrazepam can be decreased when combined with Acetohexamide.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Flunitrazepam.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
  • Avoid alcohol.
  • Avoid grapefruit products.
  • Limit caffeine intake.
  • Take with food.

Products

International/Other Brands
Hipnosedon (Roche) / Hypnodorm (Alphapharm) / Narcozep (Roche) / Rohypnol (Roche) / Roipnol (Roche)

Categories

ATC Codes
N05CD03 — Flunitrazepam
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,4-benzodiazepines. These are organic compounds containing a benzene ring fused to a 1,4-azepine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
1,4-benzodiazepines
Alternative Parents
Alpha amino acids and derivatives / Nitroaromatic compounds / Fluorobenzenes / Aryl fluorides / Tertiary carboxylic acid amides / Lactams / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Organic oxoazanium compounds / Azacyclic compounds
show 5 more
Substituents
1,4-benzodiazepine / Allyl-type 1,3-dipolar organic compound / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / C-nitro compound / Carbonyl group
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
620X0222FQ
CAS number
1622-62-4
InChI Key
PPTYJKAXVCCBDU-UHFFFAOYSA-N
InChI
InChI=1S/C16H12FN3O3/c1-19-14-7-6-10(20(22)23)8-12(14)16(18-9-15(19)21)11-4-2-3-5-13(11)17/h2-8H,9H2,1H3
IUPAC Name
5-(2-fluorophenyl)-1-methyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one
SMILES
CN1C2=C(C=C(C=C2)[N+]([O-])=O)C(=NCC1=O)C1=CC=CC=C1F

References

Synthesis Reference

Kariss, J. and Newmark, H.L.; U.S. Patent 3,116,203; December 31, 1963; assigned to Hoffmann-la Roche Inc.
 Kariss, J. and Newmark, H.L.; US. Patent 3,123,529; March 3,1964; assigned to Hoffmann-La Roche Inc. 
Keiler, O., Steiger, N. and Sternbach, L.H.; U.S. Patent 3,203,990; August 31, 1965; assigned to Hoffmann-La Roche Inc.

General References
  1. Rickels K: The clinical use of hypnotics: indications for use and the need for a variety of hypnotics. Acta Psychiatr Scand Suppl. 1986;332:132-41. [PubMed:2883820]
  2. Robertson MD, Drummer OH: Postmortem drug metabolism by bacteria. J Forensic Sci. 1995 May;40(3):382-6. [PubMed:7782744]
  3. Oelschlager H: [Chemical and pharmacologic aspects of benzodiazepines]. Schweiz Rundsch Med Prax. 1989 Jul 4;78(27-28):766-72. [PubMed:2570451]
  4. Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A: Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull. 2002 Apr;25(4):441-5. [PubMed:11995921]
  5. Tokunaga S, Takeda Y, Shinomiya K, Hirase M, Kamei C: Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats. J Pharmacol Sci. 2007 Feb;103(2):201-6. Epub 2007 Feb 8. [PubMed:17287588]
Human Metabolome Database
HMDB0015510
KEGG Drug
D01230
PubChem Compound
3380
PubChem Substance
46504553
ChemSpider
3263
BindingDB
25878
RxNav
4460
ChEBI
31622
ChEMBL
CHEMBL13280
ZINC
ZINC000003812994
Therapeutic Targets Database
DAP000931
PharmGKB
PA164781320
Wikipedia
Flunitrazepam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet1 mg
Tablet, coatedOral1 mg
Tablet, film coatedOral1 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)166-167 °CKariss, J. and Newmark, H.L.; U.S. Patent 3,116,203; December 31, 1963; assigned to Hoffmann-la Roche Inc.
 Kariss, J. and Newmark, H.L.; US. Patent 3,123,529; March 3,1964; assigned to Hoffmann-La Roche Inc. 
Keiler, O., Steiger, N. and Sternbach, L.H.; U.S. Patent 3,203,990; August 31, 1965; assigned to Hoffmann-La Roche Inc.
logP2.06HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00858 mg/mLALOGPS
logP2.2ALOGPS
logP2.55ChemAxon
logS-4.6ALOGPS
pKa (Strongest Basic)1.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area78.49 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity82.55 m3·mol-1ChemAxon
Polarizability29.6 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9922
Blood Brain Barrier+0.973
Caco-2 permeable+0.5257
P-glycoprotein substrateSubstrate0.6717
P-glycoprotein inhibitor INon-inhibitor0.6428
P-glycoprotein inhibitor IINon-inhibitor0.9094
Renal organic cation transporterNon-inhibitor0.713
CYP450 2C9 substrateNon-substrate0.7621
CYP450 2D6 substrateNon-substrate0.8932
CYP450 3A4 substrateSubstrate0.725
CYP450 1A2 substrateNon-inhibitor0.5691
CYP450 2C9 inhibitorNon-inhibitor0.5163
CYP450 2D6 inhibitorNon-inhibitor0.8776
CYP450 2C19 inhibitorInhibitor0.5957
CYP450 3A4 inhibitorInhibitor0.5626
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5555
Ames testAMES toxic0.9108
CarcinogenicityNon-carcinogens0.7209
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.8125 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9869
hERG inhibition (predictor II)Non-inhibitor0.8074
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-01p9-2393000000-5d873203e4acf1211838
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-03di-0009000000-d3cdbd0e6db0ff7d3658
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-02t9-0098000000-ed4fc29ca5e103e7e7ac
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-014i-0292000000-910e58767edf9829ae76
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0590000000-f32a6119c0a1af4b09f1
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0009000000-0917b69ebd96bce7d228
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0009000000-52198b26a21902b1164d
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-02t9-0095000000-6905e6ef41a999c5c6bb
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-014r-0291000000-05daa60855227774f98a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-01p9-0590000000-1dc724d4ffca2a0dcc87
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0230-0970000000-c801330e64d95e44fce8
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00si-1920000000-6d855cf670784a504122
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-2910000000-ab0a5646c93755d78538
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0gx0-3900000000-0e0998c190e076f40d1b

Targets

Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Positive allosteric modulator
Curator comments
The GABA(A) receptor is pentameric (i.e. comprising 5 subunit proteins) and therefore has a multitude of potential isoforms. The above target is a collection of all possible GABA(A) subunits that may participate in the formation of the pentameric receptor and is not meant to imply direct a drug-protein interaction for each individual subunit.
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [PubMed:23038269]
  2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [PubMed:29950725]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
Curator comments
Benzodiazepines modulate GABA(A) function by binding at the interface between alpha (α) and gamma (γ) subunits. Of the 6 α-subunits, only 4 (α-1, -2, -3, and -5) participate in the formation of this binding site. The above target is a collection of all α- and γ-subunits that are known to participate in the formation of the benzodiazepine binding site.
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [PubMed:23038269]
  2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [PubMed:29950725]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Gafni I, Busto UE, Tyndale RF, Kaplan HL, Sellers EM: The role of cytochrome P450 2C19 activity in flunitrazepam metabolism in vivo. J Clin Psychopharmacol. 2003 Apr;23(2):169-75. [PubMed:12640218]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Thomassin J, Tephly TR: Photoaffinity labeling of rat liver microsomal morphine UDP-glucuronosyltransferase by [3H]flunitrazepam. Mol Pharmacol. 1990 Sep;38(3):294-8. [PubMed:2119476]
  2. Cheng Z, Rios GR, King CD, Coffman BL, Green MD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci. 1998 Sep;45(1):52-7. [PubMed:9848110]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Hesse LM, Venkatakrishnan K, von Moltke LL, Shader RI, Greenblatt DJ: CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam. Drug Metab Dispos. 2001 Feb;29(2):133-40. [PubMed:11159802]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Tassaneeyakul W, Birkett DJ, Miners JO: Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents. Xenobiotica. 1998 Mar;28(3):293-301. doi: 10.1080/004982598239579 . [PubMed:9574817]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Cheng Z, Rios GR, King CD, Coffman BL, Green MD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci. 1998 Sep;45(1):52-7. [PubMed:9848110]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. Cheng Z, Rios GR, King CD, Coffman BL, Green MD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci. 1998 Sep;45(1):52-7. [PubMed:9848110]

Drug created on July 31, 2007 07:10 / Updated on June 12, 2020 11:41

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