Details of the Drug Combination

General Information of Drug Combination (ID: DCF2YHO)

• Drug Combination Name: Fentanyl + Oxycodone
• Indication: Pain, Postoperative; Status: Phase 1 [1]
• Component Drugs:
  Fentanyl (DM8WAHT): Small molecular drug
  Oxycodone (DMXLKHV): 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 Oxycodone

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Approved	[7]
Pain	MG30-MG3Z	Approved	[8]
Back pain	ME84.Z	Phase 3	[9]

Oxycodone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[20]
Opioid receptor delta (OPRD1)	TT27RFC	OPRD_HUMAN	Agonist	[21]

Oxycodone Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[22]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[22]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Coughing Responses at Tracheal Extubation	DCU1U36	N. A.	Phase 1	[23]

References

• [1] ClinicalTrials.gov (NCT03529201) QLB After Nephrectomy
• [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] Oxycodone FDA Label
• [8] 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: 7093).
• [9] ClinicalTrials.gov (NCT01427283) A Study of Oxycodone/Naloxone Controlled-release Tablets (OXN) to Assess Analgesic Efficacy and Management of Opioid-induced Constipation (OIC) in Opioid-experienced Subjects With Moderate to Severe Chronic Low Back Pain. U.S. National Institutes of Health.
• [10] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [11] 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.
• [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] 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. (Target id: 319).
• [21] Oxycodone: a pharmacological and clinical review. Clin Transl Oncol. 2007 May;9(5):298-307.
• [22] Chronic oxycodone induces integrated stress response in rat brain. BMC Neurosci. 2015 Sep 16;16:58. doi: 10.1186/s12868-015-0197-8.
• [23] ClinicalTrials.gov (NCT03204045) Comparison of the Effects of Oxycodone Versus Fentanyl on Airway Reflex to Tracheal Extubation and Postoperative Pain