Details of the Drug Combination

General Information of Drug Combination (ID: DCVAQBE)

• Drug Combination Name: Ketamine + Lidocaine
• Indication: Postoperative Pain; Status: Phase 3 [1]
• Component Drugs:
  Ketamine (DMT5HA4): Small molecular drug
  Lidocaine (DML4ZOT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ketamine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]
Anxiety	N.A.	Approved	[3]
Bipolar disorder	6A60	Approved	[3]
Depression	6A70-6A7Z	Approved	[3]
Traumatic brain injury	NA07.Z	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Chronic pain	MG30	Investigative	[3]

Ketamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
N-methyl-D-aspartate receptor (NMDAR)	TT9IK2Z	NOUNIPROTAC	Antagonist	[9]

Ketamine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[10]

Ketamine Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[11]
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Increases Expression	[8]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[8]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[12]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[12]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[8]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[13]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[8]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[14]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[15]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[16]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[16]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[8]
Protein S100-A4 (S100A4)	OTLRGFSQ	S10A4_HUMAN	Increases Expression	[8]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[16]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Increases Expression	[8]
TGF-beta receptor type-2 (TGFBR2)	OT3P7GZP	TGFR2_HUMAN	Increases Expression	[8]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[17]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Increases Expression	[14]
Leptin receptor (LEPR)	OT9H7G0C	LEPR_HUMAN	Decreases Expression	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[17]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[17]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[8]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Localization	[17]
Sodium/hydrogen exchanger 6 (SLC9A6)	OT5N47TC	SL9A6_HUMAN	Decreases Expression	[15]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Decreases Response To Substance	[18]

Indication(s) of Lidocaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[5]
Carpal tunnel syndrome	N.A.	Approved	[6]
Interstitial cystitis	GC00.3	Approved	[6]
Long QT syndrome	BC65.0	Approved	[6]
Pain	MG30-MG3Z	Approved	[6]
Pediculus capitis infestation	1G00.0	Approved	[6]
Periodontitis	DA0C	Approved	[6]
Postherpetic neuralgia	1E91.5	Approved	[6]
Pthirus pubis infestation	N.A.	Approved	[6]
Dysmenorrhea	GA34.3	Phase 2	[7]
Chronic pain	MG30	Investigative	[6]
Neuralgia	N.A.	Investigative	[6]
Premature ejaculation	HA03.0Z	Investigative	[6]
Pruritus	EC90	Investigative	[6]

Lidocaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.9 (SCN11A)	TTN9VTF	SCNBA_HUMAN	Blocker	[20]

Lidocaine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[21]

Lidocaine Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[23]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[24]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[25]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[26]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[26]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[24]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[24]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[24]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[27]

Lidocaine Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Ethylation	[28]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Methylation	[29]
Alpha-1-acid glycoprotein 1 (ORM1)	OTZKSBRE	A1AG1_HUMAN	Affects Binding	[30]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases ADR	[31]
Glutathione hydrolase 1 proenzyme (GGT1)	OTYDA1Z7	GGT1_HUMAN	Increases ADR	[31]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases ADR	[31]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Expression	[32]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[33]
Kininogen-1 (KNG1)	OT4X9LDE	KNG1_HUMAN	Decreases Activity	[34]
Beta-nerve growth factor (NGF)	OTOLABJT	NGF_HUMAN	Decreases Expression	[19]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[35]
Neurofilament medium polypeptide (NEFM)	OT8VCBNF	NFM_HUMAN	Decreases Expression	[19]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[30]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[36]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Decreases Expression	[36]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[37]
Neuronatin (NNAT)	OTNRLO7G	NNAT_HUMAN	Decreases Expression	[19]
Transient receptor potential cation channel subfamily V member 1 (TRPV1)	OTHHDR03	TRPV1_HUMAN	Increases Activity	[38]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Increases Sulfation	[39]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Affects Binding	[40]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases ADR	[31]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Affects Response To Substance	[41]
Sulfotransferase 1B1 (SULT1B1)	OTH0RQYA	ST1B1_HUMAN	Increases Sulfation	[39]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Septic Shock	DCECJVF	N. A.	Phase 3	[42]

References

• [1] ClinicalTrials.gov (NCT01983020) Peri-Operative Lidocane, Ketamine, or Lidocane and Ketamine Combination, Infusion for Patients Undergoing Spine Surgery
• [2] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 076092.
• [3] Ketamine FDA Label
• [4] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [5] 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: 2623).
• [6] Lidocaine FDA Label
• [7] ClinicalTrials.gov (NCT00651313) Efficacy and Safety Study of Lidocaine Vaginal Gel for Recurrent Dysmenorrhea (Painful Periods). U.S. National Institutes of Health.
• [8] Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-1. Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F961-F972. doi: 10.1152/ajprenal.00686.2016. Epub 2017 Mar 22.
• [9] Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64.
• [10] Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002 Jul;30(7):853-8.
• [11] Cytoskeleton interruption in human hepatoma HepG2 cells induced by ketamine occurs possibly through suppression of calcium mobilization and mitochondrial function. Drug Metab Dispos. 2009 Jan;37(1):24-31.
• [12] Ketamine hypertension and the renin-angiotensin system. Clin Exp Hypertens A. 1983;5(6):875-83. doi: 10.3109/10641968309081814.
• [13] Cellular consequences triggered by ketamine on exposure to human glioblastoma epithelial (LN-229) cells. J Biochem Mol Toxicol. 2023 Dec;37(12):e23484. doi: 10.1002/jbt.23484. Epub 2023 Jul 29.
• [14] Ketamine cystitis as a mimic of carcinoma in situ. Histopathology. 2009 Dec;55(6):705-8. doi: 10.1111/j.1365-2559.2009.03437.x.
• [15] Ketamine promotes the amyloidogenic pathway by regulating endosomal pH. Toxicology. 2022 Apr 15;471:153163. doi: 10.1016/j.tox.2022.153163. Epub 2022 Apr 1.
• [16] Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway. Toxicol In Vitro. 2023 Jun;89:105581. doi: 10.1016/j.tiv.2023.105581. Epub 2023 Mar 11.
• [17] Apoptotic insults to human HepG2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondria-caspase protease pathway. Br J Anaesth. 2009 Jan;102(1):80-9. doi: 10.1093/bja/aen322. Epub 2008 Nov 9.
• [18] The apolipoprotein E epsilon 4 allele is associated with blunting of ketamine-induced psychosis in schizophrenia. A preliminary report. Neuropsychopharmacology. 1998 Nov;19(5):445-8. doi: 10.1016/S0893-133X(98)00031-1.
• [19] Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation. J Toxicol Sci. 2021;46(7):329-339. doi: 10.2131/jts.46.329.
• [20] Mechanisms of analgesia of intravenous lidocaine. Rev Bras Anestesiol. 2008 May-Jun;58(3):280-6.
• [21] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [22] Pharmacokinetics of lidocaine hydrochloride metabolized by CYP3A4 in Chinese Han volunteers living at low altitude and in native Han and Tibetan Chinese volunteers living at high altitude. Pharmacology. 2016;97(3-4):107-13.
• [23] Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218.
• [24] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [25] Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug Metab Dispos. 2000 Aug;28(8):959-65.
• [26] Drug Interactions Flockhart Table
• [27] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
• [28] The effect of mild and moderate hepatic impairment on the pharmacokinetics of valdecoxib, a selective COX-2 inhibitor. Eur J Clin Pharmacol. 2005 Jun;61(4):247-56.
• [29] Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos. 2004 Dec;32(12):1434-45. doi: 10.1124/dmd.104.001313. Epub 2004 Sep 21.
• [30] Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
• [31] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [32] Sensitivity of human dental pulp cells to eighteen chemical agents used for endodontic treatments in dentistry. Odontology. 2013 Jan;101(1):43-51.
• [33] Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
• [34] Effects of capsaicin, bradykinin and prostaglandin E2 in the human skin. Br J Dermatol. 1992 Feb;126(2):111-7. doi: 10.1111/j.1365-2133.1992.tb07806.x.
• [35] [Influence of lidocaine on systemic inflammation in perioperative patients undergoing cardiopulmonary bypass]. Beijing Da Xue Xue Bao Yi Xue Ban. 2005 Dec 18;37(6):622-4.
• [36] 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.
• [37] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [38] The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons. J Clin Invest. 2008 Feb;118(2):763-76. doi: 10.1172/JCI32751.
• [39] Studies on sulfation of synthesized metabolites from the local anesthetics ropivacaine and lidocaine using human cloned sulfotransferases. Drug Metab Dispos. 1999 Sep;27(9):1057-63.
• [40] 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.
• [41] Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. Circ Res. 2008 Aug 15;103(4):396-404. doi: 10.1161/CIRCRESAHA.108.172619. Epub 2008 Jul 3.
• [42] ClinicalTrials.gov (NCT03640468) Lidocaine as an Adjuvant for Ketamine in Induction of Anesthesia in Septic Shock Patients