Delorazepam

Identification

Summary

Delorazepam is a benzodiazepine used to manage severe anxiety disorders and insomnia.

Generic Name
Delorazepam
DrugBank Accession Number
DB01511
Background

Delorazepam is a benzodiazepine which, like other drugs in its class, possesses anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties. It may have adverse effects such as drowsiness, and cognitive impairments such as short term memory impairment.

Delorazepam is an active metabolite of the benzodiazepine known as cloxazolam. It is a long acting benzodiazepine which makes it superior in this sense to lorazepam which is short acting. Lorazepam is also a major active metabolite of delorazepam.

In addition to be long acting, delorazepam is relatively potent, with 1 mg of delorazepam being the equivalent of 10 mg diazepam. It has been approved for marketing in Italy.

Type
Small Molecule
Groups
Experimental, Illicit
Structure
Weight
Average: 305.159
Monoisotopic: 304.017018366
Chemical Formula
C15H10Cl2N2O
Synonyms
  • Chlordesmethyldiazepam
  • Clordesmetildiazepam
  • Delorazepam
  • Delorazepamum
External IDs
  • Ro 5-3027
  • RV-12165

Pharmacology

Indication

Mainly used as an anti-anxiety agent. Studies have found delorazepam to be more effective in the first 4 weeks of use than antidepressants; however, after 4 weeks, antidepressants showed superior anti-anxiety effects. Anti-anxiety effects also appear to be weaker in elderly patients.

Effectiveness has also been observed in the treatment of alcohol withdrawal. Delorazapam was reported to be a manageable drug in that it did not exhibit severe side effects and did not require further therapies to control symptoms of withdrawal.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAnxiety•••••••••••••••••••••• ••••••••
Treatment ofAnxiety••••••••••••••••••••• ••••••
Treatment ofEpilepsies•••••••••••••••••••••• ••••••••
Treatment ofInsomnia••••••••••••••••••••• ••••••
Treatment ofSleep disorder•••••••••••••••••••••• ••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

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

77-87% oral bioavailability, with a relatively slow absorption rate. Reaches peak plasma levels within 1-2 hours of administration. Food may slow absorption, however other pharmacokinetic variables remain unchanged. After multiple doses delorazepam accumulates, although accumulation is slower in younger patients.

Volume of distribution

140 L/kg apparent volume of distribution in 11 patients with normal renal function; 47 L/kg in 11 patients with renal failure and on regular hemodialysis.

In another study, apparent volume of distribution was 65 L/kg in 8 patients with liver disease and 118.4 L/kg in 12 healthy controls.

Protein binding

>90% protein bound.

Metabolism

Delorazepam is metabolized at a relatively slow pace by the liver. The major metabolite (15-34% of the parent drug) is lorazepam. Older patients metabolize delorazepam slower than younger patients.

Route of elimination

Renally eliminated.

Half-life

Very long elimination half life of 80-115 hours, varying with age. Elimination is slower as age increases. [1] Liver disease also impacts elimination half life, with impairment resulting in half lives up to 395 hours.

Clearance

Still detectable 72 hours after dosing in healthy patients. Patients with liver disease experienced a reduction in clearance from 0.13 to 0.25 ng/mLh.

Adverse Effects
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Toxicity

Older patients metabolize delorazepam slower than younger patients and thus suffer from more adverse effects.

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
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Delorazepam is combined with 1,2-Benzodiazepine.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Delorazepam.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Delorazepam.
AgomelatineThe risk or severity of CNS depression can be increased when Delorazepam is combined with Agomelatine.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Delorazepam.
Food Interactions
Not Available

Products

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International/Other Brands
Delorazepam Almus (Almus) / Delorazepam Alter (Alter) / Delorazepam Aurobindo (Aurobindo) / Delorazepam DOC (DOC Generici) / Delorazepam EG (EG) / Delorazepam Germed (Germed Pharma) / Delorazepam Hexal (Hexal) / Delorazepam Mylan (Mylan) / Delorazepam Pensa (Pensa Pharma) / Delorazepam Ranbaxy (Ranbaxy Italia) / Delorazepam ratiopharm (Ratiopharm Italia) / Delorazepam Sandoz (Sandoz) / Delorazepam Teva (Teva Italia,) / Delorazepam Winthrop (Sanofi Winthrop) / EN (Abbott)

Categories

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 / Chlorobenzenes / Aryl chlorides / Secondary carboxylic acid amides / Lactams / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds / Organochlorides
show 3 more
Substituents
1,4-benzodiazepine / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
O91W32476G
CAS number
2894-67-9
InChI Key
CHIFCDOIPRCHCF-UHFFFAOYSA-N
InChI
InChI=1S/C15H10Cl2N2O/c16-9-5-6-13-11(7-9)15(18-8-14(20)19-13)10-3-1-2-4-12(10)17/h1-7H,8H2,(H,19,20)
IUPAC Name
7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one
SMILES
ClC1=CC2=C(NC(=O)CN=C2C2=CC=CC=C2Cl)C=C1

References

General References
  1. Bareggi SR, Nielsen NP, Leva S, Pirola R, Zecca L, Lorini M: Age-related multiple-dose pharmacokinetics and anxiolytic effects of delorazepam (chlordesmethyldiazepam). Int J Clin Pharmacol Res. 1986;6(4):309-14. [Article]
  2. Bareggi SR, Pirola R, Potvin P, Devis G: Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam. Eur J Clin Pharmacol. 1995;48(3-4):265-8. [Article]
  3. Cazzato G, Gioseffi M, Torre P, Coppola N: [Prevention and therapy of delirium tremens with tiapride and chlordesmethyldiazepam]. Riv Neurol. 1982 Nov-Dec;52(6):331-42. [Article]
  4. Scarone S, Strambi LF, Cazzullo CL: Effects of two dosages of chlordesmethyldiazepam on mnestic-information processes in normal subjects. Clin Ther. 1981;4(3):184-91. [Article]
  5. Sennesael J, Verbeelen D, Vanhaelst L, Pirola R, Bareggi SR: Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis. Eur J Clin Pharmacol. 1991;41(1):65-8. [Article]
KEGG Drug
D07784
PubChem Compound
17925
PubChem Substance
46504957
ChemSpider
16929
BindingDB
50026858
ChEBI
135295
ChEMBL
CHEMBL268254
ZINC
ZINC000001255325
Drugs.com
Drugs.com Drug Page
Wikipedia
Delorazepam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableCompletedTreatmentAnorexia Nervosa (AN) / Bulimia Nervosa1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral0.5 MG
TabletOral1 MG
TabletOral2 MG
Solution / dropsOral1 MG/ML
Solution / dropsOral
TabletOral
Injection, solutionIntramuscular; Intravenous0.5 MG/1ML
Injection, solutionIntramuscular; Intravenous1 MG/ML
Injection, solutionIntramuscular; Intravenous2 MG/1ML
Injection, solutionIntramuscular; Intravenous5 MG/1ML
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP3.15HANSCH,C & LEO,AJ (1985)
Predicted Properties
PropertyValueSource
Water Solubility0.00642 mg/mLALOGPS
logP3.46ALOGPS
logP3.82Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)12.29Chemaxon
pKa (Strongest Basic)2.05Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area41.46 Å2Chemaxon
Rotatable Bond Count1Chemaxon
Refractivity81.5 m3·mol-1Chemaxon
Polarizability29.44 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9928
Caco-2 permeable+0.8835
P-glycoprotein substrateSubstrate0.5944
P-glycoprotein inhibitor INon-inhibitor0.7784
P-glycoprotein inhibitor IINon-inhibitor0.9457
Renal organic cation transporterNon-inhibitor0.5927
CYP450 2C9 substrateNon-substrate0.7891
CYP450 2D6 substrateNon-substrate0.9139
CYP450 3A4 substrateSubstrate0.7492
CYP450 1A2 substrateInhibitor0.9347
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorNon-inhibitor0.7822
CYP450 2C19 inhibitorInhibitor0.7114
CYP450 3A4 inhibitorNon-inhibitor0.7519
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6921
Ames testNon AMES toxic0.9163
CarcinogenicityNon-carcinogens0.7766
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.1516 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9954
hERG inhibition (predictor II)Non-inhibitor0.8771
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
GC-MS Spectrum - EI-BGC-MSsplash10-0fb9-6794000000-90a56d756980bc170dc2
Mass Spectrum (Electron Ionization)MSsplash10-0fb9-3594000000-3da2aad1da4843c38183
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0009000000-5f93d3c39f2dc9415528
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0029000000-b41e430a8b70a96945dc
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0009000000-50f2ff53da3e7d3f4f7b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f89-9008000000-da25195722d3d96e1a8d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-002p-0190000000-ccfa3b75cf908b502f79
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9010000000-f2c1f0b7e1b9bc461050
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-162.2707
predicted
DeepCCS 1.0 (2019)
[M+H]+164.66628
predicted
DeepCCS 1.0 (2019)
[M+Na]+170.68677
predicted
DeepCCS 1.0 (2019)

Targets

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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. [Article]
  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. [Article]
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. [Article]
  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. [Article]

Drug created at July 31, 2007 13:10 / Updated at May 05, 2021 20:30