Identification

Name
Levobupivacaine
Accession Number
DB01002  (APRD00110)
Type
Small Molecule
Groups
Approved, Investigational
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
  • (-)-Bupivacaine
  • (S)-1-Butyl-2',6'-pipecoloxylidide
  • (S)-Bupivacaine
  • L-(-)-1-Butyl-2',6'-pipecoloxylidide
  • L-(-)-Bupivacaine
  • Levobupivacaína
  • Levobupivacaine
Product Ingredients
IngredientUNIICASInChI Key
Levobupivacaine hydrochlorideJ998RDZ51I27262-48-2SIEYLFHKZGLBNX-NTISSMGPSA-N
International/Other Brands
Chirocaine (Abbott Laboratories)
Categories
UNII
A5H73K9U3W
CAS number
27262-47-1
Weight
Average: 288.4277
Monoisotopic: 288.220163528
Chemical Formula
C18H28N2O
InChI Key
LEBVLXFERQHONN-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

Pharmacology

Indication

For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management

Pharmacodynamics

Levobupivacaine, 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 action

Local 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.

TargetActionsOrganism
ASodium channel protein type 10 subunit alpha
inhibitor
Human
Absorption

The 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 elimination

Following 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 life

3.3 hours

Clearance

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

Toxicity

LD50: 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
PathwayCategory
Levobupivacaine Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Levobupivacaine.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Levobupivacaine.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Levobupivacaine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Levobupivacaine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Levobupivacaine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Levobupivacaine.
6-Deoxyerythronolide BThe metabolism of Levobupivacaine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Levobupivacaine.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Levobupivacaine.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Levobupivacaine.
Food Interactions
Not 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 References
  1. Burlacu CL, Buggy DJ: Update on local anesthetics: focus on levobupivacaine. Ther Clin Risk Manag. 2008 Apr;4(2):381-92. [PubMed:18728849]
  2. 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]
External Links
Human Metabolome Database
HMDB0015137
KEGG Compound
C07887
PubChem Compound
92253
PubChem Substance
46505295
ChemSpider
83289
BindingDB
50350791
ChEBI
6149
ChEMBL
CHEMBL1201193
Therapeutic Targets Database
DAP001233
PharmGKB
PA164754741
RxList
RxList Drug Page
Wikipedia
Levobupivacaine
ATC Codes
N01BB10 — Levobupivacaine
FDA label
Download (2.72 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentLabour1
2CompletedPreventionAdverse Effects / Therapeutic Agent Toxicity1
2CompletedPreventionEffects of; Anesthesia, in Labor and Delivery1
2CompletedSupportive CareInguinal Hernias / Undescended Testis1
2CompletedTreatmentAnaesthesia therapy1
2RecruitingTreatmentPostoperative Cognitive Dysfunction1
2RecruitingTreatmentPostoperative pain1
2WithdrawnTreatmentEpisiotomy1
2, 3CompletedPreventionRecovery After Cleft Palate Surgery1
2, 3CompletedPreventionTransversus Abdominis Plane Block / Transversus Abdominis Plane Block, Pediatric Laparoscopy1
2, 3SuspendedTreatmentIntractable Abdominal Pain Secondary to Inoperable Malignancy1
2, 3Unknown StatusSupportive CareStillborn Caesarean Section1
3CompletedPreventionNormal Pregnancies1
3CompletedTreatmentAnalgesia, Postoperative1
3CompletedTreatmentElective Caesarean Section Surgeries1
3CompletedTreatmentPain NOS1
3CompletedTreatmentPostoperative pain1
3RecruitingTreatmentLumbar epidural anesthesia therapy1
3TerminatedNot AvailableSurgical Pathology of the Leg or the Foot1
3TerminatedPreventionPain NOS2
3WithdrawnTreatmentOrthopedic Disorder of Spine1
4Active Not RecruitingSupportive CarePostoperative pain1
4Active Not RecruitingTreatmentArterial Hypotension / Bradycardia / Tumors, Breast1
4Active Not RecruitingTreatmentInguinal Hernias / Spinal Anaesthesia1
4Active Not RecruitingTreatmentLaparoscopic Cholecystectomy / Postoperative pain1
4CompletedNot AvailableAnaesthesia / Caudal epidural block therapy / Orthopaedic Disorders1
4CompletedNot AvailableGeneral Surgery / Hallux Valgus1
4CompletedNot AvailablePain NOS1
4CompletedBasic SciencePostoperative pain1
4CompletedPreventionArterial Hypotension1
4CompletedPreventionPerioperative/Postoperative Complications1
4CompletedSupportive CareCognitive Function Abnormal / Intraoperative Monitoring / Vitreoretinal Surgery1
4CompletedSupportive CarePost-Operative Nausea and Vomiting (PONV) / Postoperative pain1
4CompletedSupportive CarePreeclampsia1
4CompletedTreatmentAnalgesia, Postoperative / Heart Surgery Via Sternotomy1
4CompletedTreatmentAnalgesia / Pain NOS / Systemic Inflammatory Stress Response1
4CompletedTreatmentBenign Prostatic Hyperplasia (BPH)1
4CompletedTreatmentCholecystolithiasis / Pain NOS / Regional Anesthesia Morbidity1
4CompletedTreatmentCholecystolithiasis / Postoperative pain1
4CompletedTreatmentComplication of Anesthesia1
4CompletedTreatmentCoronary Artery Bypass Graft Surgery Patients / Lumbar epidural anesthesia therapy1
4CompletedTreatmentEpisiotomy / Post-partum Perineal Pain / Vaginal Tear1
4CompletedTreatmentHigh Blood Pressure (Hypertension)1
4CompletedTreatmentLower Limb Surgery1
4CompletedTreatmentNeoplasms, Brain1
4CompletedTreatmentOsteoarthritis (OA)1
4CompletedTreatmentOther Peripheral Nerve Disease1
4CompletedTreatmentPain NOS3
4CompletedTreatmentGallstone formation / Pain NOS1
4CompletedTreatmentPatients Undergoing Lower Limb Surgery1
4CompletedTreatmentPostoperative pain / Postoperative Pain Following Cesarean Section1
4CompletedTreatmentPostoperative pain2
4CompletedTreatmentRegional Anesthesia1
4CompletedTreatmentThis Study Was Focused on Selective Spinal Anesthesia for Lower Extremity Surgery in Order to Achieve Early Mobilization and to Shorten Hospital Stay1
4Not Yet RecruitingTreatmentHead and Neck Carcinoma / Pain, Musculoskeletal1
4RecruitingPreventionAnaesthesia therapy / Hip Fractures1
4RecruitingSupportive CareCancer, Breast / Modified Radical Mastectomy1
4RecruitingSupportive CarePhrenic Nerve Palsy1
4RecruitingTreatmentLocal Anesthesia1
4RecruitingTreatmentNeuromuscular Block1
4RecruitingTreatmentRegional Anesthesia1
4SuspendedTreatmentPain NOS1
4TerminatedTreatmentArthroplasty, Replacement, Knee / Pain NOS1
4TerminatedTreatmentPostoperative pain / Reaction; Anesthesia1
4Unknown StatusNot AvailableFracture of Neck of Femur1
4Unknown StatusTreatmentAnalgesia, Patient-Controlled / Arthroplasty, Replacement, Knee1
4Unknown StatusTreatmentKnee Replacement Surgery1
4Unknown StatusTreatmentPatients to Benefit a Planned Femoropopliteal Bypass Through PAOD (Peripheral Arterial Occlusive Disease) Stage II or III1
4Unknown StatusTreatmentSpinal Anaesthesia1
4Unknown StatusTreatmentTotal Hip Arthroplasty (THA)1
4WithdrawnTreatmentCaesarean Sections1
Not AvailableActive Not RecruitingPreventionArterial Hypotension1
Not AvailableActive Not RecruitingTreatmentPostoperative pain1
Not AvailableCompletedNot AvailableKnee Osteoarthritis (Knee OA)1
Not AvailableCompletedNot AvailablePostoperative pain1
Not AvailableCompletedDiagnosticAnaesthesia therapy1
Not AvailableCompletedSupportive CareFemoroacetabular Impingement1
Not AvailableCompletedSupportive CarePain Insensitivity, Congenital1
Not AvailableCompletedTreatmentAdverse Reaction to Spinal Anesthetic1
Not AvailableCompletedTreatmentOsteoarthritis (OA)1
Not AvailableCompletedTreatmentPost-Operative Nausea and Vomiting (PONV) / Post-Operative Pain / Postoperative Complications1
Not AvailableCompletedTreatmentReconstruction Breast Surgery1
Not AvailableCompletedTreatmentUltrasound Therapy; Complications1
Not AvailableEnrolling by InvitationSupportive CareCancer, Breast / Radical Mastectomy Surgery1
Not AvailableEnrolling by InvitationTreatmentArthropathy1
Not AvailableNot Yet RecruitingPreventionPostoperative pain / Ureter Stone1
Not AvailableNot Yet RecruitingSupportive CareTracheal Reconstruction1
Not AvailableRecruitingTreatmentLabour Pain1
Not AvailableUnknown StatusHealth Services ResearchPregnancy1
Not AvailableWithdrawnTreatmentPostoperative pain1

Pharmacoeconomics

Manufacturers
  • Purdue pharma lp
Packagers
  • Ben Venue Laboratories Inc.
  • Purdue Pharma LP
Dosage forms
Not Available
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5708011No1994-10-132014-10-13Us

Properties

State
Solid
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 RuleNoChemAxon
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 inhibitorNon-inhibitor0.9099
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.6205
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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 piperidinecarboxamides. These are compounds containing a piperidine ring substituted with a carboxamide functional group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Piperidinecarboxylic acids and derivatives
Direct Parent
Piperidinecarboxamides
Alternative Parents
m-Xylenes / Trialkylamines / Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Hydrocarbon derivatives
Substituents
2-piperidinecarboxamide / Piperidinecarboxamide / M-xylene / Xylene / Monocyclic benzene moiety / Benzenoid / Tertiary aliphatic amine / Tertiary amine / Carboximidic acid / Carboximidic acid derivative
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (CHEBI:6149)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference acro...
Gene Name
SCN10A
Uniprot ID
Q9Y5Y9
Uniprot Name
Sodium channel protein type 10 subunit alpha
Molecular Weight
220623.605 Da
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:17139284]
  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:17016423]
  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:16418020]
  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:10969308]
  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:11094008]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Gurbuzel M, Karaca U, Karayilan N: Genotoxic evaluation of bupivacaine and levobupivacaine in the Drosophila wing spot test. Cytotechnology. 2016 Aug;68(4):979-86. doi: 10.1007/s10616-015-9852-2. Epub 2015 Feb 19. [PubMed:25693764]
  3. Chalkiadis GA, Anderson BJ, Tay M, Bjorksten A, Kelly JJ: Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age. Br J Anaesth. 2005 Oct;95(4):524-9. doi: 10.1093/bja/aei218. Epub 2005 Aug 12. [PubMed:16100236]
  4. Bajwa SJ, Kaur J: Clinical profile of levobupivacaine in regional anesthesia: A systematic review. J Anaesthesiol Clin Pharmacol. 2013 Oct;29(4):530-9. doi: 10.4103/0970-9185.119172. [PubMed:24249993]

Drug created on June 13, 2005 07:24 / Updated on November 05, 2018 17:48