Details of the Drug Combination

General Information of Drug Combination (ID: DCID1BL)

• Drug Combination Name: Fentanyl + Naltrexone
• Indication: Pain, Postoperative; Status: Phase 1 [1]
• Component Drugs:
  Fentanyl (DM8WAHT): Small molecular drug
  Naltrexone (DMUL45H): 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	[11]

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	[12]

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	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[15]

Fentanyl Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[16]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Phosphorylation	[17]
Phospholipase D2 (PLD2)	OT86I3WH	PLD2_HUMAN	Increases Activity	[18]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[19]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Expression	[18]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[20]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[18]
Beta-arrestin-2 (ARRB2)	OTAEJZCI	ARRB2_HUMAN	Affects Localization	[21]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[18]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[22]
Opioid growth factor receptor (OGFR)	OTROS6RJ	OGFR_HUMAN	Increases ADR	[23]
Adenylate cyclase type 1 (ADCY1)	OTSLLFZO	ADCY1_HUMAN	Increases ADR	[23]

Indication(s) of Naltrexone

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Chronic alcoholism	6C40.2Z	Approved	[7]
Crohn disease	DD70	Approved	[8]
Gastroparesis	DA41.00	Approved	[8]
Inflammatory bowel disease	DD72	Approved	[8]
Obesity	5B81	Approved	[8]
Ulcerative colitis	DD71	Approved	[8]
Human immunodeficiency virus infection	1C62	Phase 4	[9]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[10]
Chronic pain	MG30	Investigative	[8]

Naltrexone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Antagonist	[24]

Naltrexone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[25]

Naltrexone Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Activity	[26]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[27]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[27]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Affects Response To Substance	[24]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[24]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[28]
Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)	OTAOZIGX	GBRB2_HUMAN	Affects Response To Substance	[29]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[29]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Response To Substance	[29]

References

• [1] ClinicalTrials.gov (NCT01750060) Pharmacokinetic Characterization of the Active, Separated System With PK Controller (Fentanyl Iontophoretic Transdermal System, 40 Mcg Fentanyl Per Activation).
• [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] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074918.
• [8] Naltrexone FDA Label
• [9] 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: 1639).
• [10] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [11] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [12] 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.
• [13] Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33.
• [14] 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.
• [15] Drug Interactions Flockhart Table
• [16] 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.
• [17] 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.
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• [21] Functional and structural characterization of axonal opioid receptors as targets for analgesia. Mol Pain. 2016 Mar 1;12:1744806916628734. doi: 10.1177/1744806916628734. Print 2016.
• [22] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [23] 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.
• [24] An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008 Feb;65(2):135-44.
• [25] In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat. Biochem Pharmacol. 2008 Sep 1;76(5):672-9.
• [26] Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-4.
• [27] Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients. J Clin Endocrinol Metab. 1995 May;80(5):1739-42. doi: 10.1210/jcem.80.5.7745028.
• [28] Association between the Stin2 VNTR polymorphism of the serotonin transporter gene and treatment outcome in alcohol-dependent patients. Alcohol Alcohol. 2008 Sep-Oct;43(5):516-22. doi: 10.1093/alcalc/agn048. Epub 2008 Jun 14.
• [29] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.