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], [2]
Pain	MG30-MG3Z	Phase 2	[3]

• Therapeutic Class: Anesthetics
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 288.4
  Topological Polar Surface Area (xlogp); 3.4
  Rotatable Bond Count (rotbonds); 5
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 2
• 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 [7]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 13.00112 micromolar/kg/day [8]
  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]
• 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

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]

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]

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

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]	[45]

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]	[46]
Desipramine	DMT2FDC	Minor	Increased plasma concentration of Bupivacaine and Desipramine due to competitive binding of plasma proteins.	Attention deficit hyperactivity disorder [6A05]	[47]
Telithromycin	DMZ4P3A	Moderate	Decreased metabolism of Bupivacaine caused by Telithromycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[48]
Tucatinib	DMBESUA	Moderate	Decreased metabolism of Bupivacaine caused by Tucatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[49]
Aprepitant	DM053KT	Moderate	Decreased metabolism of Bupivacaine caused by Aprepitant mediated inhibition of CYP450 enzyme.	Depression [6A70-6A7Z]	[50]
Stiripentol	DMMSDOY	Moderate	Decreased metabolism of Bupivacaine caused by Stiripentol mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[51]
Tazemetostat	DMWP1BH	Moderate	Increased metabolism of Bupivacaine caused by Tazemetostat mediated induction of CYP450 enzyme.	Follicular lymphoma [2A80]	[52]
Delavirdine	DM3NF5G	Minor	Decreased metabolism of Bupivacaine caused by Delavirdine mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[53]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Bupivacaine caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[54]
Selpercatinib	DMZR15V	Moderate	Decreased metabolism of Bupivacaine caused by Selpercatinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[55]
Prilocaine	DMI7DZ2	Major	Increased risk of methemoglobinemia by the combination of Bupivacaine and Prilocaine.	Pain [MG30-MG3Z]	[56]
Meperidine	DMX4GND	Minor	Increased plasma concentration of Bupivacaine and Meperidine due to competitive binding of plasma proteins.	Pain [MG30-MG3Z]	[47]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Bupivacaine caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[57]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Bupivacaine caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[58]
Temsirolimus	DMS104F	Moderate	Increased plasma concentrations of Bupivacaine and Temsirolimus due to competitive inhibition of the same metabolic pathway.	Renal cell carcinoma [2C90]	[59]
Ibutilide	DMKXY2R	Moderate	Increased risk of atrioventricular block by the combination of Bupivacaine and Ibutilide.	Supraventricular tachyarrhythmia [BC81]	[60]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Bupivacaine caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[61]
Sirolimus	DMGW1ID	Moderate	Increased plasma concentrations of Bupivacaine and Sirolimus due to competitive inhibition of the same metabolic pathway.	Transplant rejection [NE84]	[59]
Tacrolimus	DMZ7XNQ	Moderate	Increased plasma concentrations of Bupivacaine and Tacrolimus due to competitive inhibition of the same metabolic pathway.	Transplant rejection [NE84]	[59]
Bretylium	DM1FX74	Moderate	Increased risk of atrioventricular block by the combination of Bupivacaine and Bretylium.	Ventricular tachyarrhythmia [BC71]	[60]
Amiodarone	DMUTEX3	Moderate	Increased risk of bradycardia by the combination of Bupivacaine and Amiodarone.	Ventricular tachyarrhythmia [BC71]	[60]

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] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 071810.
• [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] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [8] 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
• [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] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [12] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [13] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [14] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [15] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [16] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [17] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [18] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [19] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [20] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [21] Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
• [22] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [23] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [24] Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
• [25] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [26] Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
• [27] Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
• [28] High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
• [29] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [30] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [31] CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
• [32] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [33] Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
• [34] Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
• [35] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [36] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [37] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [38] Structures of muO-conotoxins from Conus marmoreus. I nhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian senso... J Biol Chem. 2004 Jun 11;279(24):25774-82.
• [39] Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
• [40] Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23. Neuropharmacology. 2004 Mar;46(3):425-38.
• [41] Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. II. Genetic approaches to pain therapy. Am J Physiol Gastrointest Liver Physiol. 2000 Apr;278(4):G507-12.
• [42] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [43] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [44] Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis. PLoS One. 2015; 10(3): e0119067.
• [45] Kharasch ED, Thummel KE "Human alfentanil metabolism by cytochrome P450 3A3/4. An explanation for the interindividual variability in alfentanil clearance?" Anesth Analg 76 (1993): 1033-9. [PMID: 8484504]
• [46] Product Information. Multaq (dronedarone). sanofi-aventis , Bridgewater, NJ.
• [47] Ghoneim MM, Pandya H "Plasma protein binding of bupivacaine and its interaction with other drugs in man." Br J Anaesth 46 (1974): 435-8. [PMID: 4458761]
• [48] Product Information. Ketek (telithromycin). Aventis Pharmaceuticals, Bridgewater, NJ.
• [49] Product Information. Tukysa (tucatinib). Seattle Genetics Inc, Bothell, WA.
• [50] Product Information. Emend (aprepitant). Merck & Company Inc, West Point, PA.
• [51] EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports.".
• [52] Product Information. Tazverik (tazemetostat). Epizyme, Inc, Cambridge, MA.
• [53] Barry M, Mulcahy F, Merry C, Gibbons S, Back D "Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection." Clin Pharmacokinet 36 (1999): 289-304. [PMID: 10320951]
• [54] Product Information. Lorbrena (lorlatinib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
• [55] Product Information. Retevmo (selpercatinib). Lilly, Eli and Company, Indianapolis, IN.
• [56] Cerner Multum, Inc. "Australian Product Information.".
• [57] Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
• [58] Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
• [59] Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
• [60] Keidar S, Grenadier E, Palant A "Sinoatrial arrest due to lidocaine injection in sick sinus syndrome during amiodarone administration." Am Heart J 104 (1982): 1384-5. [PMID: 7148661]
• [61] Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.