Details of the Drug Combination

General Information of Drug Combination (ID: DCFEH6M)

• Drug Combination Name: Fentanyl + Lidocaine
• Indication: Coronary Artery Disease; Status: Phase 4 [1]
• Component Drugs:
  Fentanyl (DM8WAHT): Small molecular drug
  Lidocaine (DML4ZOT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fentanyl

Disease Entry	ICD 11	Status	REF
Analgesia	MB40.8	Approved	[2]
Traumatic brain injury	NA07.Z	Approved	[3]
Cancer related pain	MG30	Phase 3	[4]
Pain	MG30-MG3Z	Phase 3	[5]
Chronic pain	MG30	Phase 1	[6]

Fentanyl Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[10]

Fentanyl Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]

Fentanyl Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[13]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[14]

Fentanyl Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[15]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Phosphorylation	[16]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[17]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[18]
Opioid growth factor receptor (OGFR)	OTROS6RJ	OGFR_HUMAN	Increases ADR	[19]

Indication(s) of Lidocaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[7]
Carpal tunnel syndrome	N.A.	Approved	[8]
Interstitial cystitis	GC00.3	Approved	[8]
Long QT syndrome	BC65.0	Approved	[8]
Pain	MG30-MG3Z	Approved	[8]
Pediculus capitis infestation	1G00.0	Approved	[8]
Periodontitis	DA0C	Approved	[8]
Postherpetic neuralgia	1E91.5	Approved	[8]
Pthirus pubis infestation	N.A.	Approved	[8]
Dysmenorrhea	GA34.3	Phase 2	[9]
Chronic pain	MG30	Investigative	[8]
Neuralgia	N.A.	Investigative	[8]
Premature ejaculation	HA03.0Z	Investigative	[8]
Pruritus	EC90	Investigative	[8]

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	[21]

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	[11]

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	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[14]
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	[26]

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	[27]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases ADR	[19]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases ADR	[19]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[28]
Neurofilament medium polypeptide (NEFM)	OT8VCBNF	NFM_HUMAN	Decreases Expression	[20]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[27]
Neuronatin (NNAT)	OTNRLO7G	NNAT_HUMAN	Decreases Expression	[20]
Transient receptor potential cation channel subfamily V member 1 (TRPV1)	OTHHDR03	TRPV1_HUMAN	Increases Activity	[29]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Affects Response To Substance	[30]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Transient Neurologic Syndrome	DCU67I2	N. A.	Phase 1	[31]

References

• [1] ClinicalTrials.gov (NCT02683707) The Platelet Aggregation After tiCagrelor Inhibition and FentanYl Trial (PACIFY)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Fentanyl FDA Label
• [4] ClinicalTrials.gov (NCT00822614) Safety of Fentanyl TAIFUN Treatment. U.S. National Institutes of Health.
• [5] A Phase III study to assess the clinical utility of low-dose fentanyl transdermal system in patients with chronic nonmalignant pain. Curr Med Res Opin. 2006 Aug;22(8):1493-501.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] 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).
• [8] Lidocaine FDA Label
• [9] ClinicalTrials.gov (NCT00651313) Efficacy and Safety Study of Lidocaine Vaginal Gel for Recurrent Dysmenorrhea (Painful Periods). U.S. National Institutes of Health.
• [10] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
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• [12] Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33.
• [13] Pharmacogenomics as molecular autopsy for forensic toxicology: genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. J Anal Toxicol. 2005 Oct;29(7):590-8.
• [14] Drug Interactions Flockhart Table
• [15] P-Glycoprotein on Blood-Brain Barrier Plays a Vital Role in Fentanyl Brain Exposure and Respiratory Toxicity in Rats. Toxicol Sci. 2018 Jul 1;164(1):353-362. doi: 10.1093/toxsci/kfy093.
• [16] A G protein-biased ligand at the ?-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.
• [17] Serum beta-endorphin response to stress before and after operation under fentanyl anesthesia in neonates, infants and preschool children. Eur J Pediatr Surg. 2010 Mar;20(2):106-10. doi: 10.1055/s-0029-1243620. Epub 2010 Jan 18.
• [18] opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol. 2013 Oct 15;263(1-2):35-42. doi: 10.1016/j.jneuroim.2013.07.012. Epub 2013 Jul 25.
• [19] 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.
• [20] 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.
• [21] Mechanisms of analgesia of intravenous lidocaine. Rev Bras Anestesiol. 2008 May-Jun;58(3):280-6.
• [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] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] ClinicalTrials.gov (NCT01794247) Intrathecal Magnesium for Same-day-surgery