Details of the Drug Combination

General Information of Drug Combination (ID: DCCIZZ4)

• Drug Combination Name: Fentanyl + Ropivacaine
• Indication: Congenital Skelectal Anomaly; Status: Phase 1 [1]
• Component Drugs:
  Fentanyl (DM8WAHT): Small molecular drug
  Ropivacaine (DMSPJG2): 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	[9]

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	[10]

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	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[13]

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	[14]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Phosphorylation	[15]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[16]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[17]
Opioid growth factor receptor (OGFR)	OTROS6RJ	OGFR_HUMAN	Increases ADR	[18]

Indication(s) of Ropivacaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[7]
Appendicitis	DB10	Approved	[8]

Ropivacaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.8 (SCN10A)	TT90XZ8	SCNAA_HUMAN	Modulator	[20]

Ropivacaine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[22]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[23]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[23]

Ropivacaine Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[24]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[25]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Increases Cleavage	[26]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[26]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Upper Extremity	DCA86WI	N. A.	Phase 4	[27]
Breakthrough Pain	DC9UP3E	N. A.	Phase 3	[28]
Horner's Syndrome	DCQ804I	N. A.	Phase 1	[29]

References

• [1] ClinicalTrials.gov (NCT02375191) A Comparative Study of the Effect of Epidural Dexmedetomidine Versus Fentanyl Added to Ropivacaine in Pediatric Orthopedic Surgery
• [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: 7602).
• [8] Ropivacaine FDA Label
• [9] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [10] 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.
• [11] Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33.
• [12] 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.
• [13] Drug Interactions Flockhart Table
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Ropivacaine inhibits proliferation?and invasion?and promotes apoptosis and autophagy in bladder cancer cells via inhibiting PI3K/AKT pathway. J Biochem Mol Toxicol. 2023 Jan;37(1):e23233. doi: 10.1002/jbt.23233. Epub 2022 Oct 3.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology. 1995 Jan;82(1):214-20.
• [22] Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther. 1998 Nov;64(5):484-91.
• [23] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [24] Effect of parthanatos on ropivacaine-induced damage in SH-SY5Y cells. Clin Exp Pharmacol Physiol. 2017 May;44(5):586-594. doi: 10.1111/1440-1681.12730.
• [25] Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine. Cell Res. 2004 Oct;14(5):415-22. doi: 10.1038/sj.cr.7290242.
• [26] Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway. J Toxicol Sci. 2023;48(3):139-148. doi: 10.2131/jts.48.139.
• [27] ClinicalTrials.gov (NCT00724035) Ultrasound-Guided Axillary or Infraclavicular Nerve Block for Upper Limb Surgery
• [28] ClinicalTrials.gov (NCT02278601) Comparison of Regimens MPIB, CIPCEA, PCEA
• [29] ClinicalTrials.gov (NCT02130739) Horner's SD After Thoracic Epidural Block