gamma-Hydroxybutyric acid

Identification

Brand Names
Xywav
Generic Name
gamma-Hydroxybutyric acid
DrugBank Accession Number
DB01440
Background

Gamma hydroxybutyric acid, commonly abbreviated GHB, is a therapeutic drug which is illegal in multiple countries. It is currently regulated in the US and sold by Jazz Pharmaceuticals under the name Xyrem. However, it is important to note that GHB is a designated Orphan drug (in 1985). Today Xyrem is a Schedule III drug; however GHB remains a Schedule I drug and the illicit use of Xyrem falls under penalties of Schedule I. GHB is a naturally occurring substance found in the central nervous system, wine, beef, small citrus fruits and almost all other living creatures in small amounts. It is used illegally under the street names Juice, Liquid Ecstasy or simply G, either as an intoxicant, or as a date rape drug. Xyrem is a central nervous system depressant that reduces excessive daytime sleepiness and cataplexy in patients with narcolepsy.

Type
Small Molecule
Groups
Approved, Illicit, Investigational
Structure
Weight
Average: 104.1045
Monoisotopic: 104.047344122
Chemical Formula
C4H8O3
Synonyms
  • 3-carboxypropoxy acid
  • 4-hydroxy-butyric acid
  • 4-hydroxybutanoate
  • 4-hydroxybutanoic acid
  • 4-Hydroxybutyric acid
  • gamma-Hydroxybutyrate
  • GHB
  • oxy-n-butyric acid
  • Oxybate
  • γ-Hydroxybutyric acid

Pharmacology

Indication

Used as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

GHB predominantly works at two distinct binding sites in the central nervous system: it works as an agonist at the newly-characterized excitatory GHB receptor, while acting as a weak agonist at the inhibitory GABAB receptor. Since it is a naturally occurring substance, its physiological action is similar to that of some endogenous neurotransmitters in mammalian brain. GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.

Mechanism of action

GHB is present at much higher concentrations in the brain, where it activates GABA-B receptors to exert its sedative effects. With high affinity, GHB binds to excitatory GHB receptors that are densely expressed throughout the brain, including the cotex and hippocampus. There is some evidence in research that upon activation of GHB receptors in some brain areas, the excitatory neurotransmitter glutamate is released. GHB stimulates dopamin release at low concentrations by acting on the GHB receptor, and the release of dopamine occurs in a biphasic manner. At higher concentrations, GHB inhibits dopamine release by acting on the GABA-B receptors, which is followed by GHB receptor signaling and increased release of dopamine. This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. It is proposed that overtime, the level of GHB in the brain decreases below the threshold for significant GABA-B receptor activation, leading to preferential activation of GHB receptor over GABA-B receptors and enhanced wakefulness.

TargetActionsOrganism
AGamma-hydroxybutyrate (GHB) receptor
agonist
Humans
AGamma-aminobutyric acid receptor subunit beta-1
agonist
Humans
Absorption

Not Available

Volume of distribution
  • 190 to 384 mL/kg
Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. Fecal and renal excretion is negligible. 5% renal elimination.

Half-life

30 to 60 minutes

Clearance
  • apparent oral cl=9.1 mL/min/kg [healthy adults receiving a single oral dose of 25 mg/kg]
  • 4.5 mL/min/kg [cirrhotic patients without ascites receiving a single oral dose of 25 mg/kg]
  • 4.1 mL/min/kg [cirrhotic patients with ascites receiving a single oral dose of 25 mg/kg]
Adverse Effects
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Toxicity

High doses of GHB may lead to nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death in some cases.

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

Products

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Product Ingredients
IngredientUNIICASInChI Key
Calcium oxybate8W24SYD6ZI82316-97-0AZRRVLSHRWGNRS-UHFFFAOYSA-L
Magnesium oxybateG983HLV26582316-98-1QWZIZKOBUUSCLO-UHFFFAOYSA-L
Potassium oxybateS8NKF3H3KT57769-01-4TXSIWDVUJVMMKM-UHFFFAOYSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
XywavCalcium oxybate (0.234 g / mL) + Magnesium oxybate (0.096 g / mL) + Potassium oxybate (0.13 g / mL) + Sodium oxybate (0.04 g / mL)SolutionOralJazz Pharmaceuticals Ireland Limited2023-10-04Not applicableCanada flag
XywavCalcium oxybate (0.5 g/1mL) + Potassium oxybate (0.5 g/1mL) + Magnesium oxybate (0.5 g/1mL) + Sodium oxybate (0.5 g/1mL)SolutionOralJazz Pharmaceuticals, Inc.2020-11-02Not applicableUS flag
XywavCalcium oxybate (0.234 g / mL) + Magnesium oxybate (0.096 g / mL) + Potassium oxybate (0.13 g / mL) + Sodium oxybate (0.04 g / mL)SolutionOralJazz Pharmaceuticals Ireland Limited2023-10-04Not applicableCanada flag
XywavCalcium oxybate (0.5 g/1mL) + Potassium oxybate (0.5 g/1mL) + Magnesium oxybate (0.5 g/1mL) + Sodium oxybate (0.5 g/1mL)SolutionOralJazz Pharmaceuticals, Inc.2020-11-02Not applicableUS flag
XywavCalcium oxybate (0.234 g / mL) + Magnesium oxybate (0.096 g / mL) + Potassium oxybate (0.13 g / mL) + Sodium oxybate (0.04 g / mL)SolutionOralJazz Pharmaceuticals Ireland Limited2023-10-04Not applicableCanada flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
30IW36W5B2
CAS number
591-81-1
InChI Key
SJZRECIVHVDYJC-UHFFFAOYSA-N
InChI
InChI=1S/C4H8O3/c5-3-1-2-4(6)7/h5H,1-3H2,(H,6,7)
IUPAC Name
4-hydroxybutanoic acid
SMILES
OCCCC(O)=O

References

Synthesis Reference

Joseph Klosa, "Production of nonhygroscopic salts of 4-hydroxybutyric acid." U.S. Patent US4393236, issued March, 1963.

US4393236
General References
Not Available
Human Metabolome Database
HMDB0000710
KEGG Compound
C00989
PubChem Compound
3037032
PubChem Substance
46507548
ChemSpider
9984
BindingDB
50023575
RxNav
2387302
ChEBI
30830
ChEMBL
CHEMBL1342
ZINC
ZINC000001532805
Therapeutic Targets Database
DAP001522
PharmGKB
PA10819
Wikipedia
Gamma-Hydroxybutyric_acid

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceHealthy Controls / Narcolepsy With Cataplexy1
4CompletedSupportive CarePalliative Treatment1
4CompletedTreatmentNarcolepsy1
4RecruitingTreatmentIdiopathic Hypersomnia1
4RecruitingTreatmentIdiopathic Hypersomnia / Narcolepsy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • DSM Corp.
  • Jazz Pharmaceuticals
  • Orphan Medical Inc.
  • Patheon Inc.
  • Valeant Ltd.
Dosage Forms
FormRouteStrength
SolutionOral
Prices
Unit descriptionCostUnit
Xyrem 500 mg/ml oral solution5.33USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7765106Yes2010-07-272024-12-16US flag
US6780889Yes2004-08-242021-01-04US flag
CA2355293No2005-08-162019-12-22Canada flag
US8731963Yes2014-05-202023-06-17US flag
US8772306Yes2014-07-082033-09-15US flag
US9050302Yes2015-06-092033-09-15US flag
US9486426Yes2016-11-082033-09-15US flag
US10213400Yes2019-02-262033-09-15US flag
US10675258No2020-06-092033-01-11US flag
US8901173No2014-12-022033-01-11US flag
US10195168No2019-02-052033-01-11US flag
US8591922No2013-11-262033-01-11US flag
US9132107No2015-09-152033-01-11US flag
US10864181Yes2020-12-152033-09-15US flag
US11253494Yes2013-09-152033-09-15US flag
US11426373No2017-09-192037-09-19US flag
US11554102No2013-01-112033-01-11US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility494.0 mg/mLALOGPS
logP-0.63ALOGPS
logP-0.51Chemaxon
logS0.68ALOGPS
pKa (Strongest Acidic)4.44Chemaxon
pKa (Strongest Basic)-2.4Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area57.53 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity23.8 m3·mol-1Chemaxon
Polarizability10.17 Å3Chemaxon
Number of Rings0Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.7851
Blood Brain Barrier+0.9171
Caco-2 permeable+0.5539
P-glycoprotein substrateNon-substrate0.8415
P-glycoprotein inhibitor INon-inhibitor0.981
P-glycoprotein inhibitor IINon-inhibitor0.9783
Renal organic cation transporterNon-inhibitor0.9223
CYP450 2C9 substrateNon-substrate0.8341
CYP450 2D6 substrateNon-substrate0.9043
CYP450 3A4 substrateNon-substrate0.7878
CYP450 1A2 substrateNon-inhibitor0.8141
CYP450 2C9 inhibitorNon-inhibitor0.9518
CYP450 2D6 inhibitorNon-inhibitor0.9541
CYP450 2C19 inhibitorNon-inhibitor0.9642
CYP450 3A4 inhibitorNon-inhibitor0.9721
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9884
Ames testNon AMES toxic0.9331
CarcinogenicityNon-carcinogens0.7478
BiodegradationReady biodegradable0.9967
Rat acute toxicity1.7448 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9579
hERG inhibition (predictor II)Non-inhibitor0.97
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.17 KB)
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-MS (2 TMS)GC-MSsplash10-0159-2920000000-131f94186a93d0aa315d
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0a5c-9000000000-915d32c0dbd6e6d19a55
GC-MS Spectrum - GC-MSGC-MSsplash10-0159-2920000000-131f94186a93d0aa315d
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-0002-0910000000-7240955b6b16291cf793
Mass Spectrum (Electron Ionization)MSsplash10-0006-9000000000-d55d971a361b41564681
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0007-9000000000-473d3d7616649cb5a6ea
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0ab9-9000000000-f79cb160ce337f30acf5
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0007-9000000000-449932926c62cbfdf0c7
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-9000000000-73b60ae56b31fd0ed7ad
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-9000000000-845e7dca1a6c9826cf6f
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-052f-9000000000-bb843331abca0746ff11
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]-116.6572722
predicted
DarkChem Lite v0.1.0
[M-H]-130.66713
predicted
DeepCCS 1.0 (2019)
[M+H]+117.8501722
predicted
DarkChem Lite v0.1.0
[M+H]+133.4406
predicted
DeepCCS 1.0 (2019)
[M+Na]+116.8780722
predicted
DarkChem Lite v0.1.0
[M+Na]+141.61467
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Virus receptor activity
Specific Function
Riboflavin transporter. Riboflavin transport is Na(+)-independent but moderately pH-sensitive. Activity is strongly inhibited by riboflavin analogs, such as lumiflavin. Weakly inhibited by flavin a...
Gene Name
SLC52A2
Uniprot ID
Q9HAB3
Uniprot Name
Solute carrier family 52, riboflavin transporter, member 2
Molecular Weight
45776.61 Da
References
  1. Castelli MP, Mocci I, Pistis M, Peis M, Berta D, Gelain A, Gessa GL, Cignarella G: Stereoselectivity of NCS-382 binding to gamma-hydroxybutyrate receptor in the rat brain. Eur J Pharmacol. 2002 Jun 20;446(1-3):1-5. [Article]
  2. Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, Tanganelli S, Cignarella G, Gessa GL: Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid. J Neurochem. 2003 Nov;87(3):722-32. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
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...
Gene Name
GABRB1
Uniprot ID
P18505
Uniprot Name
Gamma-aminobutyric acid receptor subunit beta-1
Molecular Weight
54234.085 Da
References
  1. Maitre M, Humbert JP, Kemmel V, Aunis D, Andriamampandry C: [A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]. Med Sci (Paris). 2005 Mar;21(3):284-9. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Symporter activity
Specific Function
Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucin...
Gene Name
SLC16A7
Uniprot ID
O60669
Uniprot Name
Monocarboxylate transporter 2
Molecular Weight
52199.745 Da
References
  1. Lin RY, Vera JC, Chaganti RS, Golde DW: Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J Biol Chem. 1998 Oct 30;273(44):28959-65. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Symporter activity
Specific Function
Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucin...
Gene Name
SLC16A1
Uniprot ID
P53985
Uniprot Name
Monocarboxylate transporter 1
Molecular Weight
53943.685 Da
References
  1. Lin RY, Vera JC, Chaganti RS, Golde DW: Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J Biol Chem. 1998 Oct 30;273(44):28959-65. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Symporter activity
Specific Function
Proton-linked monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine...
Gene Name
SLC16A3
Uniprot ID
O15427
Uniprot Name
Monocarboxylate transporter 4
Molecular Weight
49468.9 Da
References
  1. Manning Fox JE, Meredith D, Halestrap AP: Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol. 2000 Dec 1;529 Pt 2:285-93. [Article]

Drug created at July 31, 2007 13:09 / Updated at October 19, 2020 08:19