Gabapentin enacarbil

Identification

Summary

Gabapentin enacarbil is a gabapentin prodrug used to treat Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).

Brand Names
Horizant
Generic Name
Gabapentin enacarbil
DrugBank Accession Number
DB08872
Background

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).

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 329.393
Monoisotopic: 329.183837593
Chemical Formula
C16H27NO6
Synonyms
  • Gabapentin enacarbil
  • Gabapentina enacarbilo
  • Gabapentine enacarbil
  • Gabapentinum enacarbilum
External IDs
  • ASP-8825
  • ASP8825
  • GSK-1838262
  • GSK1838262
  • XP 13512
  • XP-13512
  • XP13512

Pharmacology

Indication

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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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 AvailableHumans
UVoltage-dependent calcium channel subunit alpha-2/delta-2Not AvailableHumans
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.

Adverse Effects
Adverseeffects
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Toxicity

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

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 adverse effects can be increased when Gabapentin enacarbil is combined with 1,2-Benzodiazepine.
AbacavirAbacavir 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.
AcetaminophenAcetaminophen may decrease the excretion rate of Gabapentin enacarbil which could result in a higher serum level.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Gabapentin enacarbil.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Gabapentin enacarbil.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Gabapentin enacarbil which could result in a higher serum level.
AclidiniumGabapentin enacarbil may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AcrivastineGabapentin enacarbil may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Interactions
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Food Interactions
  • Take with or without food.

Products

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Active Moieties
NameKindUNIICASInChI Key
Gabapentinprodrug6CW7F3G59X60142-96-3UGJMXCAKCUNAIE-UHFFFAOYSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
HorizantTablet, extended release300 mg/1OralArbor Pharmaceuticals2013-05-01Not applicableUS flag
HorizantTablet, extended release600 mg/1OralGlaxosmithkline Inc2011-04-072014-07-22US flag0173 080620180907 15195 bd8w82
HorizantTablet, extended release300 mg/1OralREMEDYREPACK INC.2016-09-022017-09-02US flag
HorizantTablet, extended release300 mg/1OralXenoPort Inc.2013-05-012013-04-04US flag
HorizantTablet, extended release600 mg/1OralArbor Pharmaceuticals2013-05-01Not applicableUS flag53451 0101 01 nlmimage10 e73b73eb
HorizantTablet, extended release300 mg/1OralGlaxosmithkline Inc2011-12-152014-12-05US flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Acetal / Aliphatic homomonocyclic compound / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxylic acid / Carboxylic acid ester / Dicarboxylic acid or derivatives / Gamma amino acid or derivatives / Hydrocarbon derivative
show 6 more
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
carbamate ester, monocarboxylic acid, carboxylic ester, acetal (CHEBI:68840)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
75OCL1SPBQ
CAS number
478296-72-9
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

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. [Article]
  2. Bialer M: New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs. 2006 Jun;15(6):637-47. [Article]
  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. [Article]
KEGG Drug
D09539
PubChem Compound
9883933
PubChem Substance
347827805
ChemSpider
8059607
RxNav
1101333
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
4CompletedTreatmentPostoperative pain1
4CompletedTreatmentRestless Legs Syndrome (RLS)3
4Not Yet RecruitingTreatmentFacial Pain / Pain, Acute / Postoperative pain1
4RecruitingTreatmentAlzheimer's Disease (AD) / Coronavirus Disease 2019 (COVID‑19)1
4RecruitingTreatmentRLS2
4TerminatedTreatmentRestless Legs Syndrome (RLS)1
4Unknown StatusTreatmentRestless Legs Syndrome (RLS)1
3CompletedTreatmentRestless Legs Syndrome (RLS)6
3TerminatedSupportive CareCancer of Head and Neck / Narcotics Use1
2CompletedPreventionMigraine1

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)Region
US8048917No2011-11-012022-11-06US flag
US8114909No2012-02-142026-04-11US flag
US8686034No2014-04-012025-01-24US flag
US8795725No2014-08-052029-06-10US flag
US8026279No2011-09-272026-11-10US flag
US6818787No2004-11-162022-11-06US flag

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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
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
Humans
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
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]

Drug created on May 02, 2013 21:20 / Updated on February 21, 2021 18:52