Diazepam

Identification

Summary

Diazepam is a long-acting benzodiazepine with rapid onset commonly used to treat panic disorders, severe anxiety, alcohol withdrawal, and seizures.

Brand Names
Diastat, Libervant, Valium, Valtoco 5 Mg Dose Kit
Generic Name
Diazepam
DrugBank Accession Number
DB00829
Background

A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. It is used in the treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant, and in the management of alcohol withdrawal syndrome. (From Martindale, The Extra Pharmacopoeia, 30th ed, p589)

Given diazepam's storied history as a commonly used and effective medication for a variety of indications, contemporary advancements in the formulation and administration of the agent include the development and US FDA approval of an auto-injectable formulation for the rapid treatment of uncontrolled seizures in 2015-2016 7. Combining diazepam, a proven effective therapy for acute repetitive seizures, with an auto-injector designed for subcutaneous administration that is quickly and easily administered offers the potential for complete, consistent drug absorption and rapid onset of effect 7. This current development is subsequently an important addition to the rescue therapy tool chest for patients with epilepsy 7.

Type
Small Molecule
Groups
Approved, Illicit, Investigational, Vet approved
Structure
Weight
Average: 284.74
Monoisotopic: 284.071640755
Chemical Formula
C16H13ClN2O
Synonyms
  • 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
  • Diazepam
  • Methyl diazepinone
  • NRL-1
External IDs
  • NSC-169897
  • NSC-77518
  • RO 5-2807
  • RO-5-2807
  • WY-3467

Pharmacology

Indication

In general, diazepam is useful in the symptomatic management of mild to moderate degrees of anxiety in conditions dominated by tension, excitation, agitation, fear, or aggressiveness such as may occur in psychoneurosis, anxiety reactions due to stress conditions, and anxiety states with somatic expression.16

Moreover, in acute alcoholic withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, and impending acute delirium tremens.16

Furthermore, diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathologies, such as inflammation of the muscle and joints or secondary to trauma; spasticity caused by upper motor neuron disorders, such as cerebral palsy and paraplegia; athetosis and the rare "stiff man syndrome".16

Particular label information from the United Kingdom also lists particular age-specific indications, including for adults: (1) The short-term relief (2-4 weeks) only, of anxiety which is severe, disabling, or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness, (2) cerebral palsy, (3) muscle spasm, (4) as an adjunct to certain types of epilepsy (eg. myoclonus), (5) symptomatic treatment of acute alcohol withdrawal, (6) as oral premedication for the nervous dental patient, and (7) for premedication before surgery.6

In the same UK label information, diazepam is indicated in children for: (1) control of tension and irritability in cerebral spasticity in selected cases, (2) as an adjunct to the control of muscle spasm in tetanus, and for (3) oral premedication.6

A diazepam nasal spray is indicated in patients 6 years and older to treat intermittent, stereotypic episodes of frequent seizure activity that are different than the patient's usual seizure pattern.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Symptomatic treatment ofAcute agitation••••••••••••••••••••• ••••••
Symptomatic treatment ofAcute agitation•••••••••••••••••••••• ••••••••
Symptomatic treatment ofAlcohol withdrawal delirium•••••••••••••••••••••• ••••••••
Symptomatic treatment ofAlcohol withdrawal delirium••••••••••••••••••••• ••••••
Symptomatic treatment ofAlcohol withdrawal hallucinosis•••••••••••••••••••••• ••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle- relaxant, anticonvulsant and amnestic effects 15,16,6. Most of these effects are thought to result from facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system 15,16,6.

Mechanism of action

Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties 15,16,6.

Benzodiazepines, such as diazepam, bind to receptors in various regions of the brain and spinal cord. This binding increases the inhibitory effects of gamma-aminobutyric acid (GABA) 15,16,6. GABAs functions include CNS involvement in sleep induction. Also involved in the control of hypnosis, memory, anxiety, epilepsy and neuronal excitability 15,16,6.

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

After oral administration, it is considered that diazepam is rapidly and completely absorbed from the gastrointestinal tract as >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours 15,16,6.

Absorption is delayed and decreased when administered with a moderate fat meal 15. In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting 15. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting 15. This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food 15.

Volume of distribution

In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg 15.

Protein binding

Despite high binding to plasma proteins (98-99%) - mainly albumin and to a lesser extent α1-acid glycoprotein - diazepam is widely distributed into tissues and crosses the blood-brain barrier and is highly lipid soluble, which causes the initial effects to decrease rapidly as it is redistributed into fat deposits and tissues 15,16,6.

Metabolism

Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam 15,16. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam 15,16. Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation 15,16.

Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished 15,16. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose 15,16. Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam 15,16.

Hover over products below to view reaction partners

Route of elimination

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates 15,16,6.

Half-life

Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principal active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration 6. The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease 6.

Clearance

The clearance of diazepam is 20 to 30 mL/min in young adults 15,16.

Adverse Effects
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Toxicity

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation 15,16,6. In most cases only observation of vital functions is required 15,16,6.

Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support) 15,16,6.

Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease 15,16,6. Severe effects in overdose also include rhabdomyolysis and hypothermia 6. Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored 15.

In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus 15. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered 15. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus 15. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug 15.

Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates 15. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants) 15.

Diazepam passes into breast milk 15. Breastfeeding is therefore not recommended in patients receiving diazepam 15.

Safety and effectiveness in pediatric patients below the age of 6 months have not been established 15.

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated) 15. Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function 15. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function 15.

Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis 15. In such patients, a 2- to 5- fold increase in mean half-life has been reported 15. Delayed elimination has also been reported for the active metabolite desmethyldiazepam 15. Benzodiazepines are commonly implicated in hepatic encephalopathy 15. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis 15.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*3Not Available636G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*4Not Available1A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*6Not Available395G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 3A4CYP3A4*20Not Available1461_1462insAEffect InferredPoor drug metabolizer.Details
Cytochrome P450 3A4CYP3A4*26Not Available802C>TEffect InferredPoor drug metabolizer.Details

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 Diazepam is combined with 1,2-Benzodiazepine.
AbacavirDiazepam may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbametapirThe serum concentration of Diazepam can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Diazepam can be increased when combined with Abatacept.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Diazepam.
Food Interactions
  • Avoid alcohol.
  • Take on an empty stomach. Food may decrease absorption and time to therapeutic effect.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Diazepam hydrochloride6JD21U639H52468-36-7BPYZIOINRAWEQL-UHFFFAOYSA-N
Product Images
International/Other Brands
Diapam (Orion) / Nervium (Saba) / Relanium (GlaxoSmithKline)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DiastatGel15 mg / 3 mLRectalBausch Health, Canada Inc.2022-04-21Not applicableCanada flag
DiastatGel20 mg/4mLRectalBausch Health US, LLC1997-07-292023-12-31US flag
DiastatGel10 mg / 2 mLRectalBausch Health, Canada Inc.2022-04-21Not applicableCanada flag
DiastatGel2.5 mg/0.5mLRectalBausch Health US, LLC1997-07-29Not applicableUS flag
DiastatGel20 mg/5mLRectalPhysicians Total Care, Inc.1997-07-292011-06-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Bio-diazepamTablet10 mgOralBiomed Pharma2003-04-232022-07-19Canada flag
Bio-diazepamTablet5 mgOralBiomed Pharma2003-04-232022-07-19Canada flag
Bio-diazepamTablet2 mgOralBiomed Pharma2003-04-232022-07-19Canada flag
DiazepamTablet2 mg/1OralH.J. Harkins Company, Inc.2016-01-25Not applicableUS flag
DiazepamTablet10 mg/1OralAidarex Pharmaceuticals LLC1986-12-10Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
NEURINDODiazepam (2 mg) + Metamizole sodium monohydrate (500 mg)TabletYarindo Farmatama2017-09-202022-09-20Indonesia flag
NEURODIALDiazepam (2 mg) + Metamizole sodium (500 mg)Tablet, film coatedOralKimia Farma Tbk.2017-12-272024-07-05Indonesia flag
NEUROVALDiazepam (2 mg) + Metamizole sodium monohydrate (500 mg)TabletGlobal Multi Pharmalab2016-12-272021-12-27Indonesia flag
OPINEURONDiazepam (2 mg) + Metamizole sodium (500 mg)TabletOtto Pharmaceutical Industries2017-01-312024-01-28Indonesia flag
POTENSIKDiazepam (2 mg) + Metamizole sodium monohydrate (500 mg)Tablet, film coatedOralPyridam Farma Tbk2017-03-032022-03-03Indonesia flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Gabavale-5Diazepam (5 mg/1) + Choline (125 mg/1)KitOralPhysician Therapeutics Llc2011-05-07Not applicableUS flag
Topical Nerve PainDiazepam (0.1 g/100mL) + Diclofenac sodium (0.1 g/100mL) + Gabapentin (0.1 g/100mL) + Ketamine (0.1 g/100mL)CreamTopicalDr Marc's Manufacturing And Sales2016-02-232018-04-17US flag
Topical PainDiazepam (0.1 g/100mL) + Hydrocodone (0.1 g/100mL) + Ibuprofen (0.1 g/100mL) + Tramadol (0.1 g/100mL)CreamTopicalDr Marc's Manufacturing And Sales2016-02-232018-04-17US flag

Categories

ATC Codes
N05BA01 — Diazepam
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 / Benzene and substituted derivatives / Aryl chlorides / Tertiary 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 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organochlorine compound, 1,4-benzodiazepinone (CHEBI:49575)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Q3JTX2Q7TU
CAS number
439-14-5
InChI Key
AAOVKJBEBIDNHE-UHFFFAOYSA-N
InChI
InChI=1S/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3
IUPAC Name
7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
SMILES
CN1C2=C(C=C(Cl)C=C2)C(=NCC1=O)C1=CC=CC=C1

References

Synthesis Reference

Chase, G.; U.S. Patent 3,102,116; August 27, 1963; assigned to Hoffmann-La Roche Inc. Reeder, E. and Sternbach, L.H.; U.S. Patent 3,109,843; November 5, 1963; assigned to Hoffmann-La Roche lnc. Reeder, E. and Sternbach, L.H.; U.S. Patent 3,136,815; June 9, 1964; assigned to Hoffmann- La Roche Inc. Reeder, E. and Sternbach, L.H.; US. Patent 3,371,085; February 27, 1968; assigned to Hoffmann-La Roche Inc.

General References
  1. Mant A, Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D: Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database. Aust J Public Health. 1993 Dec;17(4):345-9. [Article]
  2. Earley JV, Fryer RI, Ning RY: Quinazolines and 1,4-benzodiazepines. LXXXIX: Haptens useful in benzodiazepine immunoassay development. J Pharm Sci. 1979 Jul;68(7):845-50. [Article]
  3. 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. [Article]
  4. Oishi R, Nishibori M, Itoh Y, Saeki K: Diazepam-induced decrease in histamine turnover in mouse brain. Eur J Pharmacol. 1986 May 27;124(3):337-42. [Article]
  5. McLean MJ, Macdonald RL: Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. J Pharmacol Exp Ther. 1988 Feb;244(2):789-95. [Article]
  6. Electronic Medicines Compendium: Diazepam Tablets BP 2mg Monograph [Link]
  7. Xeris Pharmaceuticals Awarded Phase I-II NIH SBIR Fast Track Grant to Advance a Stable, Non-Aqueous Diazepam, Subcutaneous Injection for Treatment of Acute Repetitive Seizures in Patients with Epilepsy: Press Release [Link]
  8. FDA Approved Drug Products Valtoco Diazepam Nasal Spray [Link]
  9. FDA Approved Drug Products: VALTOCO® (diazepam nasal spray), CIV Jan 2023 [Link]
  10. FDA Approved Drug Products: Diastat® AcuDial™ Rectal Delivery System (diazepam rectal gel) [Link]
  11. FDA Approved Drug Products: VALIUM (diazepam) tablets, for oral use [Link]
  12. FDA Approved Drug Products: DIAZEPAM AUTOINJECTOR [Link]
  13. FDA Approved Drug Products: DIAZEPAM- diazepam injection, solution [Link]
  14. FDA Approved Drug Products: DIAZEPAM- diazepam oral solution [Link]
  15. Diazepam FDA Label [File]
  16. Diazepam Canadian Product Information [File]
  17. WHO Model Prescribing Information: Drugs Used in Anaesthesia, Premedication: Diazepam [File]
Human Metabolome Database
HMDB0014967
KEGG Drug
D00293
KEGG Compound
C06948
PubChem Compound
3016
PubChem Substance
46505210
ChemSpider
2908
BindingDB
50000766
RxNav
3322
ChEBI
49575
ChEMBL
CHEMBL12
ZINC
ZINC000000006427
Therapeutic Targets Database
DNC000549
PharmGKB
PA449283
Guide to Pharmacology
GtP Drug Page
PDBe Ligand
DZP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Diazepam
PDB Entries
2bxf / 6hup / 6x3x / 8bhk
FDA label
Download (260 KB)
MSDS
Download (53.1 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4Active Not RecruitingTreatmentDental Care for Disabled1somestatusstop reasonjust information to hide
4CompletedDiagnosticPartial Epilepsy1somestatusstop reasonjust information to hide
4CompletedOtherAbuse Potential1somestatusstop reasonjust information to hide
4CompletedPreventionFebrile Convulsions1somestatusstop reasonjust information to hide
4CompletedSupportive CareCerebral Palsy (CP) / Excessive crying / Pain1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
  • Hoffmann la roche inc
  • Roxane laboratories inc
  • Valeant pharmaceuticals international
  • Abraxis pharmaceutical products
  • Baxter healthcare corp anesthesia and critical care
  • Hospira inc
  • Marsam pharmaceuticals llc
  • Parenta pharmaceuticals inc
  • Us army medical research materiel command
  • Warner chilcott div warner lambert co
  • Watson laboratories inc
  • Pharmacia and upjohn co
  • Actavis elizabeth llc
  • Barr laboratories inc
  • Dava pharmaceuticals inc
  • Duramed pharmaceuticals inc sub barr laboratories inc
  • Ferndale laboratories inc
  • Halsey drug co inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Martec usa llc
  • Mylan pharmaceuticals inc
  • Par pharmaceutical inc
  • Pioneer pharmaceuticals inc
  • Sandoz inc
  • Vintage pharmaceuticals inc
  • Quantum pharmics ltd
Packagers
  • Aidarex Pharmacuticals LLC
  • Amerisource Health Services Corp.
  • Apotheca Inc.
  • A-S Medication Solutions LLC
  • Barr Pharmaceuticals
  • Baxter International Inc.
  • Blenheim Pharmacal
  • Bryant Ranch Prepack
  • C.O. Truxton Inc.
  • Cardinal Health
  • Caremark LLC
  • Carlisle Laboratories Inc.
  • Centaur Pharmaceuticals Pvt Ltd.
  • Comprehensive Consultant Services Inc.
  • Corepharma LLC
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • DPT Laboratories Ltd.
  • Ebewe Pharma
  • F Hoffmann-La Roche Ltd.
  • General Injectables and Vaccines Inc.
  • Group Health Cooperative
  • H.J. Harkins Co. Inc.
  • Heartland Repack Services LLC
  • Hospira Inc.
  • Innoviant Pharmacy Inc.
  • Ivax Pharmaceuticals
  • Kaiser Foundation Hospital
  • Keltman Pharmaceuticals Inc.
  • Lake Erie Medical and Surgical Supply
  • Liberty Pharmaceuticals
  • Major Pharmaceuticals
  • Mckesson Corp.
  • Meridian Medical Technologies Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nucare Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmedix
  • Physicians Total Care Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Qualitest
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Remedy Repack
  • Roxane Labs
  • Shire Inc.
  • Southwood Pharmaceuticals
  • Spectrum Pharmaceuticals
  • St Mary's Medical Park Pharmacy
  • Stat Rx Usa
  • Talbert Medical Management Corp.
  • UDL Laboratories
  • United Research Laboratories Inc.
  • Va Cmop Dallas
  • Valeant Ltd.
  • Vintage Pharmaceuticals Inc.
  • Watson Pharmaceuticals
  • Wyeth Pharmaceuticals
Dosage Forms
FormRouteStrength
CapsuleOral2 MG
CapsuleOral5 MG
Injection, solutionIntravenous
Tablet, film coatedOral
TabletOral5 mg
SolutionIntravenous10 mg
InjectionIntramuscular; Intravenous10 mg/2ml
InjectionIntramuscular10 MG
InjectionIntramuscular; Intravenous5 mg/ml
TabletOral2 mg
TabletOral10 mg
GelRectal10 mg / 2 mL
GelRectal15 mg / 3 mL
GelRectal20 mg/5mL
GelRectal5 mg / 1 mL
CapsuleOral8.0000 mg
CapsuleOral10 mg
Injection, solutionIntramuscular; Intravenous
EmulsionIntramuscular; Intravenous
EmulsionIntramuscular; Intravenous5 mg / mL
GelRectal10 mg/2g
GelRectal10 mg/2mL
GelRectal2.5 mg/0.5mL
GelRectal20 mg/4mL
GelRectal20 mg/4g
InjectionIntramuscular10 mg/2mL
InjectionIntramuscular; Intravenous
InjectionIntramuscular; Intravenous5 mg/1mL
InjectionIntramuscular; Intravenous5.0 mg/1.0mL
Injection, solutionIntramuscular; Intravenous10 mg/2mL
Injection, solutionIntramuscular; Intravenous5 mg/1mL
SolutionOral5 mg/5mL
SolutionOral5 mg/1mL
TabletOral10 mg/1
TabletOral2 mg/1
TabletOral5 mg/1
Tablet, coatedOral
Tablet, film coatedOral10 mg
SolutionIntramuscular; Intravenous5 mg
TabletOral10 mg / tab
Capsule, liquid filledOral5 mg
TabletOral
LiquidIntramuscular10 mg / 2 mL
Pill
SolutionRectal
SolutionIntramuscular; Intravenous10 mg / 2 mL
SolutionIntramuscular; Intravenous5 mg / mL
Solution, concentrateOral5 mg/1mL
Tablet, coatedOral5 MG
Solution / drops; suspension / dropsOral10 MG/ML
SolutionIntramuscular; Intravenous1000000 mg
SolutionParenteral10 mg
CapsuleOral6.000 mg
KitOral
SolutionIntramuscular; Intravenous
FilmBuccal10 mg/1
FilmBuccal12.5 mg/1
FilmBuccal15 mg/1
FilmBuccal5 mg/1
FilmBuccal7.5 mg/1
InjectionParenteral10 mg
TabletOral2 mg / tab
TabletOral5 mg / tab
SolutionRectal10 MG/2.5ML
SolutionRectal5 MG/2.5ML
Tablet
Injection, solutionIntramuscular; Intravenous10 MG/1ML
Pill15 MG
Solution / dropsOral500 MG/100ML
EnemaRectal10 MG
TabletOral5.000 mg
SolutionIntravenous10.000 mg
SolutionOral1 mg / mL
Solution / dropsOral
SolutionParenteral10.000 mg
TabletOral10.000 mg
SolutionIntramuscular10 mg
SolutionIntramuscular; Intravenous10 mg
Tablet, coatedOral
Injection5 MG/ML
SyrupOral
EnemaRectal5 mg/2.5ml
EnemaRectal5 MG
SolutionParenteral10.00 mg
CreamTopical
Solution / dropsOral0.5 %
EnemaRectal
EnemaRectal4 MG/ML
Injection
Injection5 mg
Solution / dropsOral5 MG/ML
LiquidIntramuscular; Intravenous10 mg / 2 mL
Solution / dropsOral
Tablet, film coatedOral
SprayNasal10 mg/100uL
SprayNasal5 mg/100uL
SprayNasal7.5 mg/100uL
TabletOral
Injection, solution
Suppository
InjectionIntramuscular; Intravenous10 MG
Prices
Unit descriptionCostUnit
Diastat acudial 12.5-15-20 mg429.58USD each
Diastat acudial 5-7.5-10 mg kit429.58USD kit
Diastat AcuDial 10 mg Gel 1 Box Contains Two 10 mg Syringes423.95USD box
Diastat AcuDial 20 mg Gel 1 Box Contains Two 20 mg Syringes413.6USD box
Diastat 2.5 mg pedi system362.12USD each
Valium 10 mg tablet6.06USD tablet
Diazepam powder3.99USD g
Valium 5 mg tablet2.55USD tablet
Valium 2 mg tablet2.43USD tablet
Diazemuls 5 mg/ml Emulsion1.23USD ml
Diazepam 5 mg/ml0.69USD ml
Diazepam 10 mg tablet0.38USD tablet
Diazepam 5 mg tablet0.3USD tablet
Diazepam 2 mg tablet0.26USD tablet
Diazepam 5 mg/ml vial0.17USD ml
Apo-Diazepam 10 mg Tablet0.09USD tablet
Apo-Diazepam 5 mg Tablet0.07USD tablet
Apo-Diazepam 2 mg Tablet0.05USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5462740No1995-10-312013-09-17US flag
CA2171627No2006-01-312014-09-12Canada flag
US10265402No2019-04-232025-05-11US flag
US9642913No2017-05-092025-05-11US flag
US8895546No2014-11-252029-03-27US flag
US8927497No2015-01-062025-07-21US flag
US9763876No2017-09-192029-03-27US flag
US11241414No2009-03-272029-03-27US flag
US11793786No2009-03-272029-03-27US flag
US11273131No2018-06-182038-06-18US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)125-126Chase, G.; U.S. Patent 3,102,116; August 27, 1963; assigned to Hoffmann-La Roche Inc. Reeder, E. and Sternbach, L.H.; U.S. Patent 3,109,843; November 5, 1963; assigned to Hoffmann-La Roche lnc. Reeder, E. and Sternbach, L.H.; U.S. Patent 3,136,815; June 9, 1964; assigned to Hoffmann- La Roche Inc. Reeder, E. and Sternbach, L.H.; US. Patent 3,371,085; February 27, 1968; assigned to Hoffmann-La Roche Inc.
water solubility50 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.82SANGSTER (1994)
Caco2 permeability-4.32ADME Research, USCD
pKa3.4MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
Water Solubility0.0122 mg/mLALOGPS
logP2.63ALOGPS
logP3.08Chemaxon
logS-4.4ALOGPS
pKa (Strongest Basic)2.92Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area32.67 Å2Chemaxon
Rotatable Bond Count1Chemaxon
Refractivity79.81 m3·mol-1Chemaxon
Polarizability29.39 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9948
Blood Brain Barrier+0.9934
Caco-2 permeable+0.8867
P-glycoprotein substrateSubstrate0.661
P-glycoprotein inhibitor INon-inhibitor0.5557
P-glycoprotein inhibitor IINon-inhibitor0.8383
Renal organic cation transporterInhibitor0.6152
CYP450 2C9 substrateNon-substrate0.6699
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.8177
CYP450 1A2 substrateInhibitor0.8175
CYP450 2C9 inhibitorNon-inhibitor0.5562
CYP450 2D6 inhibitorNon-inhibitor0.858
CYP450 2C19 inhibitorInhibitor0.5221
CYP450 3A4 inhibitorInhibitor0.6423
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5693
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8312
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5946 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9948
hERG inhibition (predictor II)Non-inhibitor0.8734
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (10.4 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-05r0-1290000000-3f7c85c012a85c7146de
GC-MS Spectrum - CI-BGC-MSsplash10-000i-0090000000-413ec5151b3a9fd41c47
GC-MS Spectrum - EI-BGC-MSsplash10-0a4i-3690000000-3c601fed832ff090653a
GC-MS Spectrum - EI-BGC-MSsplash10-0a59-1290000000-da27f63bddb3263e0063
Mass Spectrum (Electron Ionization)MSsplash10-0a59-2490000000-41352db33c43d0b96876
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0090000000-bece36773a183e23bfff
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0490000000-fbdfb84836374f27ffc7
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0006-0950000000-75d9ab376c968b83f255
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0006-0940000000-c585bcb21e1b3008adc1
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0590000000-2c33d4fd40c36c20a4a6
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0090000000-695f91d3d5f2e1902be3
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0090000000-15d8ced2d42d3e292bb1
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0290000000-dfdaecb8b27bc1ad2c9e
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0fdx-0890000000-b77eb07ad61e288eeb19
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-0940000000-fb79dac6c46f730fb465
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-1930000000-a6412a87698303834034
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0090000000-31830c983339c0e0d918
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0090000000-1028986b8e3b82b4bf96
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0290000000-0c2338f41998da54e8c5
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0fdx-0890000000-48e88a1c67f0fc25384f
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0f6x-0940000000-ce56b132903858bd3b6b
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-1930000000-b61e92cac5094920cf32
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0590000000-e26e1398541d17b6632e
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0f7c-0590000000-541488ae806b0dbd97cb
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-0940000000-4d1f9651cdfcc7b3eda7
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-052r-0290000000-d6f262c29a34d822e0bb
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0590000000-2b62dea3c793e2686145
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-0290000000-a55f8538b17bcc2d6bc7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0290000000-b867d84dd13d808b9cc2
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0090000000-d2f9701a6e9ba10e9351
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001l-0390000000-da4affee66d3d4ea15b5
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4r-0090000000-dd59045c1101cc62b29d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0090000000-cfe2c1cbbc72c58ee318
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00kf-1980000000-b19cc10d2d3c11caf3cd
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00si-1190000000-c70701933c2bb15e2251
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]-167.7189021
predicted
DarkChem Lite v0.1.0
[M-H]-164.47304
predicted
DeepCCS 1.0 (2019)
[M+H]+167.8973021
predicted
DarkChem Lite v0.1.0
[M+H]+166.83104
predicted
DeepCCS 1.0 (2019)
[M+Na]+167.4292021
predicted
DarkChem Lite v0.1.0
[M+Na]+172.9242
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
Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity)
Specific Function
Gaba-a receptor activity

Components:
References
  1. 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]
  2. 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]
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
Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity)
Specific Function
Gaba-a receptor activity

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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function
(r)-limonene 6-monooxygenase activity
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
  2. Jung F, Richardson TH, Raucy JL, Johnson EF: Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997 Feb;25(2):133-9. [Article]
  3. Calcaterra NE, Barrow JC: Classics in chemical neuroscience: diazepam (valium). ACS Chem Neurosci. 2014 Apr 16;5(4):253-60. doi: 10.1021/cn5000056. Epub 2014 Feb 27. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:17178770, PubMed:9555064). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:12865317, PubMed:14559847). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064)
Specific Function
All-trans retinoic acid 18-hydroxylase activity
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57469.95 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
  2. Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F: Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology. 1997 Feb 14;117(1):13-23. [Article]
  3. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). 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 imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
Specific Function
(r)-limonene 6-monooxygenase activity
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55944.565 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
  2. Jung F, Richardson TH, Raucy JL, Johnson EF: Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997 Feb;25(2):133-9. [Article]
  3. Murphy A, Wilbur K: Phenytoin-diazepam interaction. Ann Pharmacother. 2003 May;37(5):659-63. doi: 10.1345/aph.1C413. [Article]
  4. Rasmussen BB, Nielsen TL, Brosen K: Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Eur J Clin Pharmacol. 1998 Nov-Dec;54(9-10):735-40. [Article]
  5. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
Specific Function
Aromatase activity
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Mei Q, Tang C, Assang C, Lin Y, Slaughter D, Rodrigues AD, Baillie TA, Rushmore TH, Shou M: Role of a potent inhibitory monoclonal antibody to cytochrome P-450 3A4 in assessment of human drug metabolism. J Pharmacol Exp Ther. 1999 Nov;291(2):749-59. [Article]
  2. Flockhart Table of Drug Interactions [Link]
  3. Diazepam Therapy and CYP2C19 Genotype [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
Specific Function
Anandamide 11,12 epoxidase activity
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Lin Y, Lu P, Tang C, Mei Q, Sandig G, Rodrigues AD, Rushmore TH, Shou M: Substrate inhibition kinetics for cytochrome P450-catalyzed reactions. Drug Metab Dispos. 2001 Apr;29(4 Pt 1):368-74. [Article]
  2. Hedrich WD, Hassan HE, Wang H: Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425. doi: 10.1016/j.apsb.2016.07.016. Epub 2016 Aug 9. [Article]
  3. Ono S, Hatanaka T, Miyazawa S, Tsutsui M, Aoyama T, Gonzalez FJ, Satoh T: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica. 1996 Nov;26(11):1155-66. doi: 10.3109/00498259609050260. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Dual cyclooxygenase and peroxidase that plays an important role in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975). Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells (Probable). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products (By similarity)
Specific Function
Heme binding
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in retinoid metabolism. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may modulate atRA signaling and clearance. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
Specific Function
Arachidonic acid epoxygenase activity
Gene Name
CYP2C18
Uniprot ID
P33260
Uniprot Name
Cytochrome P450 2C18
Molecular Weight
55710.075 Da
References
  1. Richardson TH, Griffin KJ, Jung F, Raucy JL, Johnson EF: Targeted antipeptide antibodies to cytochrome P450 2C18 based on epitope mapping of an inhibitory monoclonal antibody to P450 2C51. Arch Biochem Biophys. 1997 Feb 15;338(2):157-64. doi: 10.1006/abbi.1996.9817. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
This enzyme relationship is supported by the results of 1 in vitro study in the literature.
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
Specific Function
Arachidonic acid epoxygenase activity
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Shou M, Lu T, Krausz KW, Sai Y, Yang T, Korzekwa KR, Gonzalez FJ, Gelboin HV: Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism. Eur J Pharmacol. 2000 Apr 14;394(2-3):199-209. doi: 10.1016/s0014-2999(00)00079-0. [Article]

Carriers

Details
1. Albumin
Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function
Antioxidant activity
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Albumin
Molecular Weight
69365.94 Da
References
  1. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. [Article]
  2. Brodersen R, Honore B: Drug binding properties of neonatal albumin. Acta Paediatr Scand. 1989 May;78(3):342-6. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
Abc-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, Chiba M, Lin JH: In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results. J Pharmacol Exp Ther. 2001 Mar;296(3):723-35. [Article]
  2. Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. [Article]

Drug created at June 13, 2005 13:24 / Updated at September 07, 2024 14:25