Details of the Drug Combination

General Information of Drug Combination (ID: DC8NYX7)

• Drug Combination Name: Lidocaine + Tramadol
• Indication: Pulpitis; Status: Phase 1 [1]
• Component Drugs:
  Lidocaine (DML4ZOT): Small molecular drug
  Tramadol (DMRQD04): 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 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Ethylation	[16]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Methylation	[17]
Alpha-1-acid glycoprotein 1 (ORM1)	OTZKSBRE	A1AG1_HUMAN	Affects Binding	[18]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases ADR	[19]
Glutathione hydrolase 1 proenzyme (GGT1)	OTYDA1Z7	GGT1_HUMAN	Increases ADR	[19]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases ADR	[19]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Expression	[20]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[21]
Kininogen-1 (KNG1)	OT4X9LDE	KNG1_HUMAN	Decreases Activity	[22]
Beta-nerve growth factor (NGF)	OTOLABJT	NGF_HUMAN	Decreases Expression	[7]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[23]
Neurofilament medium polypeptide (NEFM)	OT8VCBNF	NFM_HUMAN	Decreases Expression	[7]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[18]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[24]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Decreases Expression	[24]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[25]
Neuronatin (NNAT)	OTNRLO7G	NNAT_HUMAN	Decreases Expression	[7]
Transient receptor potential cation channel subfamily V member 1 (TRPV1)	OTHHDR03	TRPV1_HUMAN	Increases Activity	[26]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Increases Sulfation	[27]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Affects Binding	[28]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases ADR	[19]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Affects Response To Substance	[29]
Sulfotransferase 1B1 (SULT1B1)	OTH0RQYA	ST1B1_HUMAN	Increases Sulfation	[27]

Indication(s) of Tramadol

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Approved	[5]
Pain	MG30-MG3Z	Approved	[6]
Chronic pain	MG30	Investigative	[5]
Premature ejaculation	HA03.0Z	Investigative	[5]

Tramadol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 2C receptor (HTR2C)	TTWJBZ5	5HT2C_HUMAN	Modulator	[30]

Tramadol Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[31]

Tramadol Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[32]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[33]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[32]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[32]

Tramadol Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[34]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Decreases Expression	[35]
Creatine kinase B-type (CKB)	OTUCKOTT	KCRB_HUMAN	Decreases Expression	[35]
NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1)	OTTIZDFR	NDUS1_HUMAN	Decreases Expression	[35]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Affects Activity	[35]
kinase isozyme 3, mitochondrial (PDK3)	OTCPSTID	PDK3_HUMAN	Increases Expression	[35]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Pain Management	DCJVZWT	N. A.	Phase 3	[36]

References

• [1] ClinicalTrials.gov (NCT05538052) Use of Tramadol Intraligamentary Injections
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• [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] Tramadol FDA Label
• [6] 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: 8286).
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• [14] Drug Interactions Flockhart Table
• [15] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
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• [21] 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.
• [22] 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.
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• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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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• [35] Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells. Toxicology. 2016 Jun 1;359-360:1-10. doi: 10.1016/j.tox.2016.06.010. Epub 2016 Jun 15.
• [36] ClinicalTrials.gov (NCT05928520) Pain Management in Pediatric Adenotonsillectomy