Details of the Drug Combination

General Information of Drug Combination (ID: DC3N734)

• Drug Combination Name: Lidocaine + Sevoflurane
• Indication: Colonic Cancer; Status: Phase 3 [1]
• Component Drugs:
  Lidocaine (DML4ZOT): Small molecular drug
  Sevoflurane (DMC9O43): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lidocaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]
Carpal tunnel syndrome	N.A.	Approved	[3]
Interstitial cystitis	GC00.3	Approved	[3]
Long QT syndrome	BC65.0	Approved	[3]
Pain	MG30-MG3Z	Approved	[3]
Pediculus capitis infestation	1G00.0	Approved	[3]
Periodontitis	DA0C	Approved	[3]
Postherpetic neuralgia	1E91.5	Approved	[3]
Pthirus pubis infestation	N.A.	Approved	[3]
Dysmenorrhea	GA34.3	Phase 2	[4]
Chronic pain	MG30	Investigative	[3]
Neuralgia	N.A.	Investigative	[3]
Premature ejaculation	HA03.0Z	Investigative	[3]
Pruritus	EC90	Investigative	[3]

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	[8]

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	[9]

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	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[14]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[12]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[12]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[12]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[15]

Lidocaine Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Alpha-1-acid glycoprotein 1 (ORM1)	OTZKSBRE	A1AG1_HUMAN	Affects Binding	[16]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases ADR	[17]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases ADR	[17]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[18]
Neurofilament medium polypeptide (NEFM)	OT8VCBNF	NFM_HUMAN	Decreases Expression	[7]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[16]
Neuronatin (NNAT)	OTNRLO7G	NNAT_HUMAN	Decreases Expression	[7]
Transient receptor potential cation channel subfamily V member 1 (TRPV1)	OTHHDR03	TRPV1_HUMAN	Increases Activity	[19]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Affects Response To Substance	[20]

Indication(s) of Sevoflurane

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]

Sevoflurane Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutamate receptor AMPA (GRIA)	TTAN6JD	NOUNIPROTAC	Antagonist	[21]

Sevoflurane Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[23]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[24]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[12]

Sevoflurane Interacts with 31 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glycine receptor subunit alpha-1 (GLRA1)	OT05Y9ZR	GLRA1_HUMAN	Increases ADR	[17]
Glutamate dehydrogenase 1, mitochondrial (GLUD1)	OTXKOCUH	DHE3_HUMAN	Increases Expression	[25]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[26]
Progonadoliberin-1 (GNRH1)	OTH8A44K	GON1_HUMAN	Increases Expression	[26]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[27]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[26]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Increases Expression	[25]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[26]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases Expression	[26]
Cyclic AMP-dependent transcription factor ATF-2 (ATF2)	OTNIZPEA	ATF2_HUMAN	Increases Phosphorylation	[28]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[25]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[25]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Increases Expression	[26]
Merlin (NF2)	OT6E5ACG	MERL_HUMAN	Increases Expression	[26]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[26]
Dual specificity mitogen-activated protein kinase kinase 3 (MAP2K3)	OTI2OREX	MP2K3_HUMAN	Increases Phosphorylation	[28]
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)	OTK13JKC	MP2K6_HUMAN	Increases Phosphorylation	[28]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Increases Expression	[26]
RNA-binding protein EWS (EWSR1)	OT7SRHV3	EWS_HUMAN	Increases Expression	[26]
Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A (MGAT5)	OTU4DD4G	MGT5A_HUMAN	Increases Expression	[26]
Metastasis-associated protein MTA1 (MTA1)	OTBHW3S9	MTA1_HUMAN	Increases Expression	[26]
Integrin alpha-7 (ITGA7)	OTTBTAYW	ITA7_HUMAN	Decreases Expression	[26]
Mothers against decapentaplegic homolog 2 (SMAD2)	OTC6VB4K	SMAD2_HUMAN	Increases Expression	[26]
KiSS-1 receptor (KISS1R)	OTQA3J6G	KISSR_HUMAN	Decreases Expression	[26]
FXYD domain-containing ion transport regulator 5 (FXYD5)	OT81DIOD	FXYD5_HUMAN	Increases Expression	[26]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Phosphorylation	[28]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[29]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[29]
Pinin (PNN)	OT0HXICH	PININ_HUMAN	Increases Expression	[26]
Programmed cell death 1 ligand 1 (CD274)	OTJ0VFDL	PD1L1_HUMAN	Decreases Expression	[30]
Mitochondrial pyruvate carrier 1 (MPC1)	OT6DYFUO	MPC1_HUMAN	Increases Expression	[25]

References

• [1] ClinicalTrials.gov (NCT04316013) Volatile Anaesthesia and Perioperative Outcomes Related to Cancer: The VAPOR-C Trial
• [2] 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).
• [3] Lidocaine FDA Label
• [4] ClinicalTrials.gov (NCT00651313) Efficacy and Safety Study of Lidocaine Vaginal Gel for Recurrent Dysmenorrhea (Painful Periods). 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: 7296).
• [6] Sevoflurane in COVID-19 ARDS (SevCov)
• [7] 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.
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• [9] 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.
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• [13] Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug Metab Dispos. 2000 Aug;28(8):959-65.
• [14] Drug Interactions Flockhart Table
• [15] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats. Can J Anaesth. 2009 Feb;56(2):126-35.
• [22] Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology. 1993 Oct;79(4):795-807.
• [23] Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology. 1995 Mar;82(3):689-99.
• [24] Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
• [25] Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms. Cell Biol Toxicol. 2023 Aug;39(4):1395-1411. doi: 10.1007/s10565-022-09766-6. Epub 2022 Oct 8.
• [26] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
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• [28] Sevoflurane-mediated activation of p38-mitogen-activated stresskinase is independent of apoptosis in Jurkat T-cells. Anesth Analg. 2008 Apr;106(4):1150-60, table of contents. doi: 10.1213/ane.0b013e3181683d37.
• [29] 4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway. Neurotoxicology. 2022 May;90:256-264. doi: 10.1016/j.neuro.2022.04.008. Epub 2022 Apr 23.
• [30] CircRNA VIM silence synergizes with sevoflurane to inhibit immune escape and multiple oncogenic activities of esophageal cancer by simultaneously regulating miR-124/PD-L1 axis. Cell Biol Toxicol. 2022 Oct;38(5):825-845. doi: 10.1007/s10565-021-09613-0. Epub 2021 May 20.