Identification

Name
Sodium oxybate
Accession Number
DB09072
Type
Small Molecule
Groups
Approved
Description

Sodium oxybate (Xyrem) is a central nervous system depressant used for the treatment of cataplexy and extreme daytime sleepiness (EDS) associated with narcolepsy. It is the sodium salt of gamma hydroxybutyric acid (GHB) which is an endogenous compound and a metabolite of the neurotransmitter GABA. The exact mechanism of action for treating EDS and cataplexy is not known but is is hypothesised that its therapeutic effects are due to GABA(B) effects on noradrenergic, dopaminaergic and thalamocorticol neurons. The drug follows non-linear pharmacokinetics. As it has been associated with misuse/abuse it is strictly controlled and all patients and prescribers must enroll in the sodium oxybate REMs program in order to gain access to the medication.

Structure
Thumb
Synonyms
  • Oxybate sodium
External IDs
NSC-84223 / WY-3478
Active Moieties
NameKindUNIICASInChI Key
Gamma hydroxybutyric acidunknown30IW36W5B2591-81-1SJZRECIVHVDYJC-UHFFFAOYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
XyremSolution500 mgOralJazz Pharmaceuticals Ireland Limited2007-08-03Not applicableCanada
XyremSolution0.5 g/1mLOralJazz Pharmaceuticals2002-07-17Not applicableUs
Categories
UNII
7G33012534
CAS number
502-85-2
Weight
Average: 126.087
Monoisotopic: 126.02928837
Chemical Formula
C4H7NaO3
InChI Key
XYGBKMMCQDZQOZ-UHFFFAOYSA-M
InChI
InChI=1S/C4H8O3.Na/c5-3-1-2-4(6)7;/h5H,1-3H2,(H,6,7);/q;+1/p-1
IUPAC Name
sodium 4-hydroxybutanoate
SMILES
[Na+].OCCCC([O-])=O

Pharmacology

Indication

For the treatment of cataplexy in narcolepsy and excessive daytime sleepiness (EDS) in narcolepsy.

Associated Conditions
Pharmacodynamics

Sodium oxybate works through an unknown mechanism to treat narcolepsy by inducing sleep within about 5-15 minutes of administration.

Mechanism of action

The exact mechanism of action is unknown. It is the sodium salt of the endogenous compound gamma hydroxybutyrate which is a metabolite of the GABA neurotransmitter and it's thought that it's therapeutic effects are mediated via GABA B actions at noradrenergic, dopaminergic and thalamocortical neurons.

Absorption

Absolute bioavailability is approximately 88%. Tmax of 30.7-51.9min [2].

Volume of distribution

Vd of 37.7-67.7 [2]

Protein binding

Less then 1% is protein bound at concentrations ranging from 3 mcg/L to 300 mcg/L.

Metabolism

Animal studies indicate that the major elimination pathway is metabolism by the creation of carbon dioxide and water through the Krebs cycle and secondarily by beta-oxidation. In the primary pathway hydroxyacid-oxoacid transhydrogenase catalyzes the conversion of sodium oxybate to succinic semialdehyde which is then transformed to succinic acid by succinic semmialdehyde dehydrogenase. Succinic acid is then turned into carbon dioxide and water in the Krebs cycle. Succinic semialdehyde is also metabolised into carbon dioxide and water by a transhydrofenase in the presence of alpha ketoglutarate.

Route of elimination

The major metabolite is carbon dioxide which is cleared by expiration, less then 5% appears as the unchanged drug in the urine within 6-8 hours after dosing.

Half life

0.5 to 1 hour.

Clearance

Total clearance of 895-1361mL/min [2].

Toxicity

Symptoms of overdose may include; depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma, emesis, diaphoresis, headache and impaired psychomotor skills. Depth of coma varies with the amount ingested and myoclonus and tonic-clonic seizures have been reported. Oral LD50 of 9690mg/kg in rats [MSDS].

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

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of 7-Nitroindazole.
AcepromazineSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Acepromazine.
AceprometazineSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Aceprometazine.
AdipiplonSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Adipiplon.
AgomelatineSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Agomelatine.
AlaproclateThe risk or severity of adverse effects can be increased when Sodium oxybate is combined with Alaproclate.
AlfaxaloneSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Alfaxalone.
AlfentanilSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Alfentanil.
AlimemazineSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Alimemazine.
AllopregnanoloneSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Allopregnanolone.
Food Interactions
Not Available

References

General References
  1. Lemon MD, Strain JD, Farver DK: Sodium oxybate for cataplexy. Ann Pharmacother. 2006 Mar;40(3):433-40; quiz 581-2. Epub 2006 Feb 28. [PubMed:16507620]
  2. Brenneisen R, Elsohly MA, Murphy TP, Passarelli J, Russmann S, Salamone SJ, Watson DE: Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects. J Anal Toxicol. 2004 Nov-Dec;28(8):625-30. [PubMed:15538955]
External Links
PubChem Compound
23663870
PubChem Substance
347827822
ChemSpider
9983
ChEMBL
CHEMBL1200682
Wikipedia
Sodium_oxybate
ATC Codes
N01AX11 — Sodium oxybateN07XX04 — Sodium oxybate
AHFS Codes
  • 28:92.00 — Miscellaneous Central Nervous System Agents
FDA label
Download (428 KB)
MSDS
Download (179 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentHypersomnia / Narcolepsy / Traumatic Brain Injury (TBI)1
1CompletedBasic ScienceNarcolepsy, Excessive Daytime Sleepiness1
1CompletedPreventionSedative Abuse1
1, 2CompletedTreatmentAlternating Hemiplegia of Childhood1
2CompletedTreatmentFibromyalgia1
2CompletedTreatmentInsomnia Related to Schizophrenia (307.42) / Schizophrenic Disorders1
2CompletedTreatmentSpasmodic Dysphonia / Voice Tremor1
2CompletedTreatmentTremor, Essential1
2Unknown StatusTreatmentSleep-wake Disturbances in Motor-phase Parkinson's Disease1
2WithdrawnTreatmentAnxiety, Post Traumatic / PTSD1
2WithdrawnTreatmentMechanically Ventilated ICU Patients1
2, 3CompletedTreatmentBinge Eating Disorder (BED)1
2, 3Not Yet RecruitingTreatmentIdiopathic Hypersomnia1
2, 3RecruitingBasic ScienceSpasmodic Dysphonia / Vocal Fold Nodules / Voice Tremor1
3Active Not RecruitingTreatmentNarcolepsy With Cataplexy1
3CompletedNot AvailableNarcolepsy1
3CompletedTreatmentFibromyalgia4
3CompletedTreatmentNarcolepsy2
3Not Yet RecruitingTreatmentCluster Headache1
3RecruitingTreatmentCataplexy / Excessive Daytime Sleepiness / Narcolepsy1
4CompletedNot AvailableMyalgic Encephalomyelitis (ME)1
4CompletedBasic ScienceSleep1
4CompletedTreatmentAlcohol Dependence / Alcohol Withdrawal Syndrome(AWS)1
4CompletedTreatmentNarcolepsy With Cataplexy1
4CompletedTreatmentObstructive Sleep Apnea Syndrome (OSAS)1
4RecruitingBasic ScienceNarcolepsy With Cataplexy1
4TerminatedTreatmentMild Alzheimer's Disease1
4TerminatedTreatmentMyalgic Encephalomyelitis (ME)1
4Unknown StatusTreatmentMyalgic Encephalomyelitis (ME)1
Not AvailableCompletedNot AvailableAutistic Disorder / Bipolar Disorder (BD) / Major Depressive Disorder (MDD)1
Not AvailableCompletedOtherAmyloid-beta1
Not AvailableCompletedTreatmentParkinson's Disease (PD)1
Not AvailableCompletedTreatmentSleep Initiation and Maintenance Disorders1
Not AvailableUnknown StatusNot AvailableOlder Adults1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionOral0.5 g/1mL
SolutionOral500 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7765106No2004-06-162024-06-16Us
US6780889No2000-07-042020-07-04Us
US7668730No2004-06-162024-06-16Us
US7765107No2004-06-162024-06-16Us
US7851506No1999-12-222019-12-22Us
US7895059No2002-12-172022-12-17Us
US8263650No1999-12-222019-12-22Us
US8324275No1999-12-222019-12-22Us
US8457988No2002-12-172022-12-17Us
US8589182No2002-12-172022-12-17Us
US8731963No2002-12-172022-12-17Us
US8772306No2013-03-152033-03-15Us
US8952062No1999-12-222019-12-22Us
US9050302No2013-03-152033-03-15Us
US7262219No2000-07-042020-07-04Us
US8859619No1999-12-222019-12-22Us
US9539330No1999-12-222019-12-22Us
US9486426No2013-03-152033-03-15Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)145-146MSDS
Predicted Properties
PropertyValueSource
Water Solubility660.0 mg/mLALOGPS
logP-0.34ALOGPS
logP-0.51ChemAxon
logS0.72ALOGPS
pKa (Strongest Acidic)4.44ChemAxon
pKa (Strongest Basic)-2.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area60.36 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity34.64 m3·mol-1ChemAxon
Polarizability9.74 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as short-chain hydroxy acids and derivatives. These are hydroxy acids with an alkyl chain the contains less than 6 carbon atoms.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Hydroxy acids and derivatives
Sub Class
Short-chain hydroxy acids and derivatives
Direct Parent
Short-chain hydroxy acids and derivatives
Alternative Parents
Fatty acids and conjugates / Carboxylic acid salts / Monocarboxylic acids and derivatives / Carboxylic acids / Primary alcohols / Organic zwitterions / Organic sodium salts / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Short-chain hydroxy acid / Fatty acid / Carboxylic acid salt / Organic alkali metal salt / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic sodium salt / Organic oxide / Organic salt
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Succinate-semialdehyde dehydrogenase [nad(p)+] activity
Specific Function
Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Gene Name
ALDH5A1
Uniprot ID
P51649
Uniprot Name
Succinate-semialdehyde dehydrogenase, mitochondrial
Molecular Weight
57214.23 Da
References
  1. Kim YG, Lee S, Kwon OS, Park SY, Lee SJ, Park BJ, Kim KJ: Redox-switch modulation of human SSADH by dynamic catalytic loop. EMBO J. 2009 Apr 8;28(7):959-68. doi: 10.1038/emboj.2009.40. Epub 2009 Mar 19. [PubMed:19300440]
Kind
Protein
Organism
Homo sapiens
Pharmacological action
No
Actions
Substrate
General Function
Metal ion binding
Specific Function
Catalyzes the cofactor-independent reversible oxidation of gamma-hydroxybutyrate (GHB) to succinic semialdehyde (SSA) coupled to reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG)...
Gene Name
ADHFE1
Uniprot ID
Q8IWW8
Uniprot Name
Hydroxyacid-oxoacid transhydrogenase, mitochondrial
Molecular Weight
50307.42 Da
References
  1. Struys EA, Verhoeven NM, Ten Brink HJ, Wickenhagen WV, Gibson KM, Jakobs C: Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias. J Inherit Metab Dis. 2005;28(6):921-30. [PubMed:16435184]

Drug created on May 14, 2015 11:10 / Updated on September 21, 2018 20:42