Identification

Name
Gabapentin enacarbil
Accession Number
DB08872  (DB04922)
Type
Small Molecule
Groups
Approved, Investigational
Description

Gabapentin enacarbil is marketed under the name Horizant. It is a prodrug of gabapentin, and indicated in adults for the treatment of Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).

Structure
Thumb
Synonyms
  • Gabapentina enacarbilo
  • Gabapentine enacarbil
  • Gabapentinum enacarbilum
External IDs
ASP-8825 / ASP8825 / GSK-1838262 / GSK1838262 / XP 13512 / XP-13512 / XP13512
Active Moieties
NameKindUNIICASInChI Key
Gabapentinprodrug6CW7F3G59X60142-96-3UGJMXCAKCUNAIE-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
HorizantTablet, extended release600 mg/1OralGlaxosmithkline Inc2011-04-072014-07-22Us0173 080620180907 15195 bd8w82
HorizantTablet, extended release300 mg/1OralArbor Pharmaceuticals2013-05-01Not applicableUs
HorizantTablet, extended release300 mg/1OralRemedy Repack2016-09-02Not applicableUs
HorizantTablet, extended release300 mg/1OralGlaxosmithkline Inc2011-12-152014-12-05Us
HorizantTablet, extended release600 mg/1OralArbor Pharmaceuticals2013-05-01Not applicableUs53451 0101 01 nlmimage10 e73b73eb
HorizantTablet, extended release300 mg/1OralXenoPort Inc.2013-05-012013-04-04Us
Categories
UNII
75OCL1SPBQ
CAS number
478296-72-9
Weight
Average: 329.393
Monoisotopic: 329.183837593
Chemical Formula
C16H27NO6
InChI Key
TZDUHAJSIBHXDL-UHFFFAOYSA-N
InChI
InChI=1S/C16H27NO6/c1-11(2)14(20)22-12(3)23-15(21)17-10-16(9-13(18)19)7-5-4-6-8-16/h11-12H,4-10H2,1-3H3,(H,17,21)(H,18,19)
IUPAC Name
2-(1-{[({1-[(2-methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl}cyclohexyl)acetic acid
SMILES
CC(C)C(=O)OC(C)OC(=O)NCC1(CC(O)=O)CCCCC1

Pharmacology

Indication

For the treatment of adult Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).

Associated Conditions
Pharmacodynamics

Since gabapentin enacarbil is a prodrug of gabapentin, it's physiological effects are the same as gabapentin. Concerning PHN, gabapentin prevents allodynia and hyperalgesia.

Mechanism of action

Although the exact mechanism of action of gabapentin in RLS and PHN is unknown, it is presumed to involve the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors.

TargetActionsOrganism
UVoltage-dependent calcium channel subunit alpha-2/delta-1Not AvailableHuman
UVoltage-dependent calcium channel subunit alpha-2/delta-2Not AvailableHuman
Absorption

Gabapentin enacarbil is absorbed in the intestines by active transport through the proton-linked monocarboxylate transporter, MCT-1.

Volume of distribution

The volume of distribution is 76L.

Protein binding

Gabapentin plasma protein binding is less than 3%.

Metabolism

Gabapentin enacarbil does not interact with any of the major cytochrome P450 enzymes.

Route of elimination

Gabapentin enacarbil is eliminated primarily in the urine (94%) and to a lesser extent in the feces (5%).

Half life

The elimination half-life of gabapentin is 5.1 to 6.0 hours.

Clearance

Renal clearance of gabapentin is 5 to 7 L/hr.

Toxicity

Most common adverse reactions are headache, dizziness, and somnolence.

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

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Gabapentin enacarbil is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Gabapentin enacarbil.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Gabapentin enacarbil.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Gabapentin enacarbil.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Gabapentin enacarbil is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Gabapentin enacarbil.
AbacavirAbacavir may decrease the excretion rate of Gabapentin enacarbil which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Gabapentin enacarbil which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Gabapentin enacarbil which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Gabapentin enacarbil which could result in a higher serum level.
Food Interactions
  • No food effects.

References

Synthesis Reference
  1. Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, Koller K, Liu X, Mann A, Panuwat M, Raillard SP, Upadhyay S, Wu QQ, Xiang JN, Yan H, Zerangue N, Zhou CX, Barrett RW, Gallop MA: XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004 Oct;311(1):315-23. Epub 2004 May 14.
General References
  1. Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, Koller K, Liu X, Mann A, Panuwat M, Raillard SP, Upadhyay S, Wu QQ, Xiang JN, Yan H, Zerangue N, Zhou CX, Barrett RW, Gallop MA: XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004 Oct;311(1):315-23. Epub 2004 May 14. [PubMed:15146028]
  2. Bialer M: New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs. 2006 Jun;15(6):637-47. [PubMed:16732716]
  3. Cundy KC, Annamalai T, Bu L, De Vera J, Estrela J, Luo W, Shirsat P, Torneros A, Yao F, Zou J, Barrett RW, Gallop MA: XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther. 2004 Oct;311(1):324-33. Epub 2004 May 14. [PubMed:15146029]
External Links
KEGG Drug
D09539
PubChem Compound
9883933
PubChem Substance
347827805
ChemSpider
8059607
ChEBI
68840
ChEMBL
CHEMBL1628502
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Gabapentin_enacarbil
FDA label
Download (347 KB)
MSDS
Download (30.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentPatients With Impaired Renal Function and Haemodialysis1
1CompletedTreatmentRestless Legs Syndrome (RLS)2
1WithdrawnTreatmentRLS1
2Active Not RecruitingTreatmentIrritability / Neurologically Impaired / Pain, Chronic / Signs and Symptoms, Digestive / Sleeplessness1
2CompletedPreventionMigraine Disorders / Migraines1
2CompletedTreatmentAlcohol Use Disorder (AUD)1
2CompletedTreatmentDiabetic Neuropathies1
2CompletedTreatmentPostherpetic Neuralgia2
2CompletedTreatmentRestless Legs Syndrome (RLS)3
2TerminatedTreatmentDiabetic Neuropathies1
2TerminatedTreatmentProstate Cancer1
3CompletedTreatmentRestless Legs Syndrome (RLS)6
3Not Yet RecruitingSupportive CareCancer of Head and Neck / Narcotic Use1
4CompletedTreatmentPostoperative pain1
4CompletedTreatmentRestless Legs Syndrome (RLS)3
4Enrolling by InvitationTreatmentRLS1
4Not Yet RecruitingTreatmentFacial Pain / Pain, Acute / Postoperative pain1
4Not Yet RecruitingTreatmentRestless Legs Syndrome (RLS)1
4RecruitingTreatmentAlzheimer's Disease (AD)1
4RecruitingTreatmentRLS1
4TerminatedTreatmentRestless Legs Syndrome (RLS)1
Not AvailableActive Not RecruitingTreatmentRestless Legs Syndrome (RLS)1
Not AvailableRecruitingNot AvailableRestless Legs Syndrome (RLS)1
Not AvailableRecruitingTreatmentPain NOS1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, extended releaseOral300 mg/1
Tablet, extended releaseOral600 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8048917No2011-11-012022-11-06Us
US8114909No2012-02-142026-04-11Us
US8686034No2014-04-012025-01-24Us
US8795725No2014-08-052029-06-10Us
US8026279No2011-09-272026-11-10Us
US6818787No2004-11-162022-11-06Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)Melting onset of about 64°C.From FDA label.
water solubilitySolubility of 0.5 mg/mL in water From FDA label.
pKapKa 5.0From The Merck Index.
Predicted Properties
PropertyValueSource
Water Solubility0.325 mg/mLALOGPS
logP2.45ALOGPS
logP2.76ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)4.35ChemAxon
pKa (Strongest Basic)-7.1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area101.93 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity81.69 m3·mol-1ChemAxon
Polarizability34.38 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
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
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Gamma amino acids and derivatives
Alternative Parents
Dicarboxylic acids and derivatives / Carbamate esters / Organic carbonic acids and derivatives / Carboxylic acid esters / Carboxylic acids / Acetals / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
Gamma amino acid or derivatives / Dicarboxylic acid or derivatives / Carbamic acid ester / Carboxylic acid ester / Carbonic acid derivative / Acetal / Carboxylic acid / Organic nitrogen compound / Organonitrogen compound / Organooxygen compound
show 6 more
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
carbamate ester, monocarboxylic acid, carboxylic ester, acetal (CHEBI:68840)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity
Specific Function
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-...
Gene Name
CACNA2D1
Uniprot ID
P54289
Uniprot Name
Voltage-dependent calcium channel subunit alpha-2/delta-1
Molecular Weight
124566.93 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity
Specific Function
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-t...
Gene Name
CACNA2D2
Uniprot ID
Q9NY47
Uniprot Name
Voltage-dependent calcium channel subunit alpha-2/delta-2
Molecular Weight
129816.095 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Symporter activity
Specific Function
Acts as an electrogenic sodium (Na(+)) and chloride (Cl-)-dependent sodium-coupled solute transporter, including transport of monocarboxylates (short-chain fatty acids including L-lactate, D-lactat...
Gene Name
SLC5A8
Uniprot ID
Q8N695
Uniprot Name
Sodium-coupled monocarboxylate transporter 1
Molecular Weight
66577.005 Da
References
  1. Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, Koller K, Liu X, Mann A, Panuwat M, Raillard SP, Upadhyay S, Wu QQ, Xiang JN, Yan H, Zerangue N, Zhou CX, Barrett RW, Gallop MA: XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004 Oct;311(1):315-23. Epub 2004 May 14. [PubMed:15146028]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sodium-dependent multivitamin transmembrane transporter activity
Specific Function
Transports pantothenate, biotin and lipoate in the presence of sodium.
Gene Name
SLC5A6
Uniprot ID
Q9Y289
Uniprot Name
Sodium-dependent multivitamin transporter
Molecular Weight
68641.27 Da
References
  1. Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, Koller K, Liu X, Mann A, Panuwat M, Raillard SP, Upadhyay S, Wu QQ, Xiang JN, Yan H, Zerangue N, Zhou CX, Barrett RW, Gallop MA: XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004 Oct;311(1):315-23. Epub 2004 May 14. [PubMed:15146028]

Drug created on May 02, 2013 15:20 / Updated on November 02, 2018 06:55