Details of the Drug

General Information of Drug (ID: DM4PRFC)

Drug Name

Bupivacaine

Synonyms

Anekain; Bloqueina; Bucaine; Bupivacaina; Bupivacainum; Bupivan; CBupivacaine; Carbostesin; DepoBupivacaine; Marcaina; Marcaine; Sensorcaine; Bupivacaine Carbonate; Bupivacaine HCL; Bupivacaine HCL KIT; Marcaine HCL; Marcaine Spinal; AH 250; Win 11318; Win 11318 HCl; Bucaine (TN); Bupivacaina [INN-Spanish]; Bupivacaine (INN); Bupivacaine Monohydrochloride, Monohydrate; Bupivacaine [INN:BAN]; Bupivacainum [INN-Latin]; DL-Bupivacaine; DUR-843; Marcain (TN); Marcaine (TN); Sensorcaine (TN); Sensorcaine-MPF; Sensorcaine-MPFSpinal; Transdur-Bupivacaine; Vivacaine (TN); Dl-1-Butyl-2',6'-pipecoloxylidide; (1)-1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide; (inverted exclamation markA)-bupivacaine; 1-Butyl-2',6'-pipecoloxylidide; 1-Butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide; 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide

Indication

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[1]
Articular cartilage disorder	FA34.Y	Approved	[2]
Periodontitis	DA0C	Approved	[2]
Pain	MG30-MG3Z	Phase 2	[3]
Chronic pain	MG30	Investigative	[2]
Pruritus	EC90	Investigative	[2]
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Therapeutic Class

Anesthetics

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

288.4

Logarithm of the Partition Coefficient (xlogp)

3.4

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 1718 +/- 1211 mcgh/L [4]
Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 54 +/- 33 mcg/L [4]
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 3 h [4]
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [5]
Clearance: The drug present in the plasma can be removed from the body at the rate of 4.3 mL/min/kg [6]
Elimination: 2% of drug is excreted from urine in the unchanged form [5]
Half-life: The concentration or amount of drug in body reduced by one-half in 2.7 hours [4]
Metabolism: The drug is metabolized via the liver []
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 13.00112 micromolar/kg/day [7]
Unbound Fraction: The unbound fraction of drug in plasma is 0.056% [6]
Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.84 L/kg [6]
Water Solubility: The ability of drug to dissolve in water is measured as 0.17 mg/mL [5]

Adverse Drug Reaction (ADR)

ADR Term	Variation	Related DOT	DOT ID	REF
Therapeutic agent toxicity	Not Available	GNB1	OTLL7L74	[8]
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Chemical Identifiers

Formula: C18H28N2O
IUPAC Name: 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide
Canonical SMILES: CCCCN1CCCCC1C(=O)NC2=C(C=CC=C2C)C
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)
InChIKey: LEBVLXFERQHONN-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 2474
ChEBI ID: CHEBI:77431
CAS Number: 38396-39-3
DrugBank ID: DB00297
TTD ID: D0A0FL
INTEDE ID: DR0243

Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Voltage-gated sodium channel alpha Nav1.8 (SCN10A)	TT90XZ8	SCNAA_HUMAN	Modulator	[9]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Substrate	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Substrate	[10]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Gene/Protein Processing	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Gene/Protein Processing	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Gene/Protein Processing	[12]
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (GNB1)	OTLL7L74	GBB1_HUMAN	Drug Response	[8]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Drug Response	[13]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Post-Translational Modifications	[14]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Post-Translational Modifications	[14]
NLR family member X1 (NLRX1)	OTEJ7ROA	NLRX1_HUMAN	Gene/Protein Processing	[11]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Gene/Protein Processing	[15]
Prostaglandin G/H synthase 1 (PTGS1)	OTHCRLEC	PGH1_HUMAN	Gene/Protein Processing	[16]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Anaesthesia

ICD Disease Classification

9A78.6

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Voltage-gated sodium channel alpha Nav1.8 (SCN10A)	DTT	SCN10A	9.89E-01	-0.16	-0.31
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	1.65E-02	-4.37E-02	-7.84E-02
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	1.21E-04	-2.33E-01	-5.09E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	6.90E-01	2.35E-02	7.88E-02

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Bupivacaine

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Alfentanil	DMVO0UB	Minor	Decreased metabolism of Bupivacaine caused by Alfentanil mediated inhibition of CYP450 enzyme.	Corneal disease [9A76-9A78]	[17]
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Coadministration of a Drug Treating the Disease Different from Bupivacaine (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Dronedarone	DMA8FS5	Moderate	Decreased metabolism of Bupivacaine caused by Dronedarone mediated inhibition of CYP450 enzyme.	Angina pectoris [BA40]	[18]
Desipramine	DMT2FDC	Minor	Increased plasma concentration of Bupivacaine and Desipramine due to competitive binding of plasma proteins.	Attention deficit hyperactivity disorder [6A05]	[19]
Telithromycin	DMZ4P3A	Moderate	Decreased metabolism of Bupivacaine caused by Telithromycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[20]
Tucatinib	DMBESUA	Moderate	Decreased metabolism of Bupivacaine caused by Tucatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[21]
Aprepitant	DM053KT	Moderate	Decreased metabolism of Bupivacaine caused by Aprepitant mediated inhibition of CYP450 enzyme.	Depression [6A70-6A7Z]	[22]
Stiripentol	DMMSDOY	Moderate	Decreased metabolism of Bupivacaine caused by Stiripentol mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[23]
Tazemetostat	DMWP1BH	Moderate	Increased metabolism of Bupivacaine caused by Tazemetostat mediated induction of CYP450 enzyme.	Follicular lymphoma [2A80]	[24]
Delavirdine	DM3NF5G	Minor	Decreased metabolism of Bupivacaine caused by Delavirdine mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[25]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Bupivacaine caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[26]
Selpercatinib	DMZR15V	Moderate	Decreased metabolism of Bupivacaine caused by Selpercatinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[27]
Prilocaine	DMI7DZ2	Major	Increased risk of methemoglobinemia by the combination of Bupivacaine and Prilocaine.	Pain [MG30-MG3Z]	[28]
Meperidine	DMX4GND	Minor	Increased plasma concentration of Bupivacaine and Meperidine due to competitive binding of plasma proteins.	Pain [MG30-MG3Z]	[19]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Bupivacaine caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[29]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Bupivacaine caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[30]
Temsirolimus	DMS104F	Moderate	Increased plasma concentrations of Bupivacaine and Temsirolimus due to competitive inhibition of the same metabolic pathway.	Renal cell carcinoma [2C90]	[31]
Ibutilide	DMKXY2R	Moderate	Increased risk of atrioventricular block by the combination of Bupivacaine and Ibutilide.	Supraventricular tachyarrhythmia [BC81]	[32]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Bupivacaine caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[33]
Sirolimus	DMGW1ID	Moderate	Increased plasma concentrations of Bupivacaine and Sirolimus due to competitive inhibition of the same metabolic pathway.	Transplant rejection [NE84]	[31]
Tacrolimus	DMZ7XNQ	Moderate	Increased plasma concentrations of Bupivacaine and Tacrolimus due to competitive inhibition of the same metabolic pathway.	Transplant rejection [NE84]	[31]
Bretylium	DM1FX74	Moderate	Increased risk of atrioventricular block by the combination of Bupivacaine and Bretylium.	Ventricular tachyarrhythmia [BC71]	[32]
Amiodarone	DMUTEX3	Moderate	Increased risk of bradycardia by the combination of Bupivacaine and Amiodarone.	Ventricular tachyarrhythmia [BC71]	[32]
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References

1	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2397).
2	Bupivacaine FDA Label
3	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
4	FDA Approved Drug Products: ZYNRELEF (bupivacaine and meloxicam) solution
5	BDDCS applied to over 900 drugs
6	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
7	Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
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9	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
10	Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. Drug Metab Dispos. 2000 Apr;28(4):383-5.
11	LncRNA SNHG12 ameliorates bupivacaine-induced neurotoxicity by sponging miR-497-5p to upregulate NLRX1. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221089001. doi: 10.1177/09603271221089001.
12	Apoptosis and mitochondrial dysfunction in human chondrocytes following exposure to lidocaine, bupivacaine, and ropivacaine. J Bone Joint Surg Am. 2010 Mar;92(3):609-18. doi: 10.2106/JBJS.H.01847.
13	H(1)R mediates local anesthetic-induced vascular permeability in angioedema. Toxicol Appl Pharmacol. 2020 Apr 1;392:114921. doi: 10.1016/j.taap.2020.114921. Epub 2020 Feb 12.
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16	The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. Anesth Analg. 2008 Jan;106(1):321-7, table of contents.
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30	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
31	Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
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