Identification

Name
gamma-Hydroxybutyric acid
Accession Number
DB01440
Type
Small Molecule
Groups
Approved, Illicit, Investigational
Description

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.

Structure
Thumb
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
Categories
UNII
30IW36W5B2
CAS number
591-81-1
Weight
Average: 104.1045
Monoisotopic: 104.047344122
Chemical Formula
C4H8O3
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

Pharmacology

Indication

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

Pharmacodynamics

GHB has at least two distinct binding sites in the central nervous system. GHB is an agonist at the newly-characterized GHB receptor, which is excitatory, and it is a weak agonist at the GABAB receptor, which is inhibitory. GHB is a naturally-occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain. GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.

Mechanism of action

GHB reaches much higher concentrations in the brain and activates GABAB receptors, which are primarily responsible for its sedative effects. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in the release of glutamate, the principal excitatory neurotransmitter. Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,[19] low concentrations stimulate dopamine release via the GHB receptor.[20] Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as baclofen and phenibut.[21] After an initial phase of inhibition, dopamine release is then increased via the GHB receptor. 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. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABAB receptor activation and activates predominantly the GHB receptor, leading to wakefulness.

TargetActionsOrganism
AGamma-hydroxybutyrate (GHB) receptor
agonist
Human
AGamma-aminobutyric acid receptor subunit beta-1
agonist
Human
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]
Toxicity

At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Butanoate MetabolismMetabolic
Glutamic Acid MetabolismMetabolic
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with 7-Nitroindazole.
AcepromazineThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Acepromazine.
AceprometazineThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Aceprometazine.
AcetazolamideThe risk or severity of adverse effects can be increased when Gamma hydroxybutyric acid is combined with Acetazolamide.
AdipiplonThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Adipiplon.
AgomelatineThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Agomelatine.
AlaproclateThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Alaproclate.
AlfaxaloneThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Alfaxalone.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Gamma hydroxybutyric acid.
AlimemazineThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Alimemazine.
Food Interactions
Not Available

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
External Links
Human Metabolome Database
HMDB0015507
KEGG Compound
C00989
PubChem Compound
3037032
PubChem Substance
46507548
ChemSpider
2300886
ChEBI
16724
Therapeutic Targets Database
DAP001522
PharmGKB
PA10819
Wikipedia
Gamma-Hydroxybutyric_acid

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAlcohol Dependence / Alcohol Withdrawal Syndrome(AWS)1
4RecruitingBasic ScienceNarcolepsy With Cataplexy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • DSM Corp.
  • Jazz Pharmaceuticals
  • Orphan Medical Inc.
  • Patheon Inc.
  • Valeant Ltd.
Dosage forms
Not Available
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)
US7765106No2004-06-162024-06-16Us
US6780889No2000-07-042020-07-04Us
CA2355293No2005-08-162019-12-22Canada

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-MSNot Available
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/MSsplash10-000i-9100000000-80636ab7e3cb47d4d58f
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-05n4-9000000000-71899633e269029ab7f9
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-9000000000-910235f5bc92bcca7469
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-8900000000-5890f0a527dd16d9ac75
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0k9i-9200000000-241210fedf9304168090
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4l-9000000000-21d09118dfcfcb093f8d

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
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. [PubMed:12098579]
  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. [PubMed:14535954]
Kind
Protein
Organism
Human
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. [PubMed:15745703]

Transporters

Kind
Protein
Organism
Human
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. [PubMed:9786900]
Kind
Protein
Organism
Human
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. [PubMed:9786900]
Kind
Protein
Organism
Human
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. [PubMed:11101640]

Drug created on July 31, 2007 07:09 / Updated on October 01, 2018 13:05