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Identification
NameLevobupivacaine
Accession NumberDB01002  (APRD00110)
TypeSmall Molecule
GroupsApproved
Description

Levobupivacaine is an amino-amide local anaesthetic drug belonging to the family of n-alkylsubstituted
pipecoloxylidide. It is the S-enantiomer of bupivacaine. Levobupivacaine hydrochloride is commonly marketed by AstraZeneca under the trade name Chirocaine. Compared to bupivacaine, levobupivacaine is associated with less vasodilation and has a longer duration of action. It is approximately 13 per cent less potent (by molarity) than racemic bupivacaine.Levobupivacaine is indicated for local anaesthesia including infiltration, nerve block, ophthalmic, epidural and intrathecal anaesthesia in adults; and infiltration analgesia in children. Adverse drug reactions (ADRs) are rare when it is administered correctly. Most ADRs relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, however allergic reactions can rarely occur. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
(-)-BupivacaineNot AvailableNot Available
(S)-1-Butyl-2',6'-pipecoloxylidideNot AvailableNot Available
(S)-BupivacaineNot AvailableNot Available
L-(-)-1-Butyl-2',6'-pipecoloxylidideNot AvailableNot Available
L-(-)-BupivacaineNot AvailableNot Available
LevobupivacaineNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
ChirocaineAbbott Laboratories
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Levobupivacaine hydrochloride
Thumb
  • InChI Key: SIEYLFHKZGLBNX-NTISSMGPSA-N
  • Monoisotopic Mass: 324.196841267
  • Average Mass: 324.889
DBSALT000834
CategoriesNot Available
CAS number27262-47-1
WeightAverage: 288.4277
Monoisotopic: 288.220163528
Chemical FormulaC18H28N2O
InChI KeyLEBVLXFERQHONN-INIZCTEOSA-N
InChI
InChI=1S/C18H28N2O/c1-4-5-12-20-13-7-6-11-16(20)18(21)19-17-14(2)9-8-10-15(17)3/h8-10,16H,4-7,11-13H2,1-3H3,(H,19,21)/t16-/m0/s1
IUPAC Name
(2S)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide
SMILES
CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentAlpha amino acid amides
Alternative Parents
Substituents
  • Alpha-amino acid amide
  • N-arylamide
  • Piperidinecarboxylic acid
  • Piperidinecarboxamide
  • 2-piperidinecarboxamide
  • Benzenoid
  • Piperidine
  • Monocyclic benzene moiety
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
  • 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (CHEBI:6149 )
Pharmacology
IndicationFor the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management
PharmacodynamicsLevobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures.
Mechanism of actionLocal anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization.
AbsorptionThe plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean Cmax levels of up to 1.2 µg/mL.
Volume of distribution

66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers]

Protein binding>97%
Metabolism

Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo.

Route of eliminationFollowing intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces.
Half life3.3 hours
Clearance

39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers]

ToxicityLD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Levobupivacaine Action PathwayDrug actionSMP00397
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9814
Blood Brain Barrier+0.936
Caco-2 permeable+0.6669
P-glycoprotein substrateSubstrate0.8435
P-glycoprotein inhibitor IInhibitor0.8582
P-glycoprotein inhibitor IINon-inhibitor0.7836
Renal organic cation transporterNon-inhibitor0.6471
CYP450 2C9 substrateNon-substrate0.7957
CYP450 2D6 substrateSubstrate0.8346
CYP450 3A4 substrateSubstrate0.7045
CYP450 1A2 substrateInhibitor0.6863
CYP450 2C9 substrateNon-inhibitor0.9099
CYP450 2D6 substrateInhibitor0.8932
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateInhibitor0.6205
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6066
Ames testNon AMES toxic0.8462
CarcinogenicityNon-carcinogens0.8859
BiodegradationNot ready biodegradable0.9729
Rat acute toxicity2.2574 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8283
hERG inhibition (predictor II)Inhibitor0.7851
Pharmacoeconomics
Manufacturers
  • Purdue pharma lp
Packagers
Dosage formsNot Available
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States57080111994-10-132014-10-13
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP3.6Not Available
pKa8.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0977 mg/mLALOGPS
logP3.31ALOGPS
logP4.52ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)13.62ChemAxon
pKa (Strongest Basic)8ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area32.34 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity90.19 m3·mol-1ChemAxon
Polarizability34.45 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Hooshang Shahriari Zavareh, Graham Anthony Charles Frampton, “Process for preparing levobupivacaine and analogues thereof.” U.S. Patent US5777124, issued February, 1985.

US5777124
General Reference
  1. Leone S, Di Cianni S, Casati A, Fanelli G: Pharmacology, toxicology, and clinical use of new long acting local anesthetics, ropivacaine and levobupivacaine. Acta Biomed. 2008 Aug;79(2):92-105. Pubmed 18788503
  2. http://www.orgyn.com/resources/genrx/D003445.asp
  3. Burlacu CL, Buggy DJ: Update on local anesthetics: focus on levobupivacaine. Ther Clin Risk Manag. 2008 Apr;4(2):381-92. Pubmed
External Links
ATC CodesN01BB10
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (2.72 MB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AtazanavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
BoceprevirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
ClarithromycinCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
DarunavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
DelavirdineCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
FosamprenavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
IndinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
ItraconazoleCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
LopinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
NefazodoneCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
NelfinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
PosaconazoleCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
RitonavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
SaquinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
TelaprevirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
TelithromycinCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
VoriconazoleCYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
Food InteractionsNot Available

Targets

1. Sodium channel protein type 10 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 10 subunit alpha Q9Y5Y9 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Ueta K, Sugimoto M, Suzuki T, Uchida I, Mashimo T: In vitro antagonism of recombinant ligand-gated ion-channel receptors by stereospecific enantiomers of bupivacaine. Reg Anesth Pain Med. 2006 Jan-Feb;31(1):19-25. Pubmed
  4. Vladimirov M, Nau C, Mok WM, Strichartz G: Potency of bupivacaine stereoisomers tested in vitro and in vivo: biochemical, electrophysiological, and neurobehavioral studies. Anesthesiology. 2000 Sep;93(3):744-55. Pubmed
  5. Brau ME, Branitzki P, Olschewski A, Vogel W, Hempelmann G: Block of neuronal tetrodotoxin-resistant Na+ currents by stereoisomers of piperidine local anesthetics. Anesth Analg. 2000 Dec;91(6):1499-505. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12