General Information of Drug Combination (ID: DCNW9WI)

Drug Combination Name
Fentanyl Flurbiprofen
Indication
Disease Entry Status REF
Sedation Complication Phase 4 [1]
Component Drugs Fentanyl   DM8WAHT Flurbiprofen   DMGN4BY
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
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 13 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]
Phospholipase D2 (PLD2) OT86I3WH PLD2_HUMAN Increases Activity [16]
Pro-opiomelanocortin (POMC) OTV41F7T COLI_HUMAN Decreases Expression [17]
Interleukin-4 (IL4) OTOXBWAU IL4_HUMAN Increases Expression [16]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Increases Expression [18]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Increases Phosphorylation [16]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Increases Phosphorylation [16]
Beta-arrestin-2 (ARRB2) OTAEJZCI ARRB2_HUMAN Affects Localization [19]
Interleukin-2 (IL2) OTGI4NSA IL2_HUMAN Decreases Expression [16]
Potassium voltage-gated channel subfamily H member 2 (KCNH2) OTZX881H KCNH2_HUMAN Decreases Activity [20]
Opioid growth factor receptor (OGFR) OTROS6RJ OGFR_HUMAN Increases ADR [21]
Adenylate cyclase type 1 (ADCY1) OTSLLFZO ADCY1_HUMAN Increases ADR [21]
------------------------------------------------------------------------------------
⏷ Show the Full List of 13 DOT(s)
Indication(s) of Flurbiprofen
Disease Entry ICD 11 Status REF
Osteoarthritis FA00-FA05 Approved [7]
Rheumatoid arthritis FA20 Approved [8]
Flurbiprofen Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Prostaglandin G/H synthase 2 (COX-2) TTVKILB PGH2_HUMAN Modulator [24]
------------------------------------------------------------------------------------
Flurbiprofen Interacts with 5 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [25]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [26]
UDP-glucuronosyltransferase 2B7 (UGT2B7) DEB3CV1 UD2B7_HUMAN Metabolism [27]
UDP-glucuronosyltransferase 1A3 (UGT1A3) DEF2WXN UD13_HUMAN Metabolism [27]
UDP-glucuronosyltransferase 1A9 (UGT1A9) DE85D2P UD19_HUMAN Metabolism [27]
------------------------------------------------------------------------------------
Flurbiprofen Interacts with 22 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 2C9 (CYP2C9) OTGLBN29 CP2C9_HUMAN Increases Hydroxylation [28]
NAD(P)H dehydrogenase 1 (NQO1) OTZGGIVK NQO1_HUMAN Increases Activity [29]
Prostaglandin G/H synthase 2 (PTGS2) OT75U9M4 PGH2_HUMAN Increases Expression [30]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [31]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [31]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Increases Expression [32]
Amyloid-beta precursor protein (APP) OTKFD7R4 A4_HUMAN Decreases Secretion [33]
Prostaglandin G/H synthase 1 (PTGS1) OTHCRLEC PGH1_HUMAN Decreases Activity [34]
Aldo-keto reductase family 1 member C3 (AKR1C3) OTU2SXBA AK1C3_HUMAN Decreases Activity [35]
Aldo-keto reductase family 1 member C2 (AKR1C2) OTQ2XMO3 AK1C2_HUMAN Decreases Activity [35]
Aldo-keto reductase family 1 member C1 (AKR1C1) OTQKR4CM AK1C1_HUMAN Decreases Activity [35]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) OTZKVLVJ CP17A_HUMAN Decreases Activity [36]
Metalloproteinase inhibitor 1 (TIMP1) OTOXC51H TIMP1_HUMAN Increases Expression [37]
Albumin (ALB) OTVMM513 ALBU_HUMAN Affects Binding [38]
Eukaryotic translation initiation factor 4E (EIF4E) OTDAWNLA IF4E_HUMAN Increases Phosphorylation [39]
Tumor necrosis factor receptor superfamily member 16 (NGFR) OTPKSM49 TNR16_HUMAN Increases Expression [40]
L-selectin (SELL) OT6RAJZR LYAM1_HUMAN Decreases Expression [41]
Matrix metalloproteinase-9 (MMP9) OTB2QDAV MMP9_HUMAN Decreases Expression [37]
15-hydroxyprostaglandin dehydrogenase (HPGD) OTYZI6JB PGDH_HUMAN Increases Expression [37]
Cytochrome P450 4A11 (CYP4A11) OTPU5J0S CP4AB_HUMAN Decreases Activity [42]
ELAV-like protein 1 (ELAVL1) OTY55PLY ELAV1_HUMAN Increases Expression [39]
Growth/differentiation factor 15 (GDF15) OTWQN50N GDF15_HUMAN Increases Expression [43]
------------------------------------------------------------------------------------
⏷ Show the Full List of 22 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Sedation Complication DCW2UU8 N. A. Phase 4 [1]
------------------------------------------------------------------------------------

References

1 ClinicalTrials.gov (NCT04602845) Remimazolam Tosilate Sedation and Midazolam Sedation in Dental Patients
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 Flurbiprofen 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: 4194).
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 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.
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 Mechanisms of the inhibition of nuclear factor-B by morphine in neuronal cells. Mol Pharmacol. 2012 Apr;81(4):587-97. doi: 10.1124/mol.111.076620. Epub 2012 Jan 18.
19 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.
20 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.
21 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.
22 Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
23 Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation. J Biol Chem. 2004 Jul 2;279(27):28320-9. doi: 10.1074/jbc.M401396200. Epub 2004 Apr 26.
24 Flurbiprofen, a cyclooxygenase inhibitor, protects mice from hepatic ischemia/reperfusion injury by inhibiting GSK-3 signaling and mitochondrial permeability transition.Mol Med.2012 Sep 25;18:1128-35.
25 Predominant contribution of UDP-glucuronosyltransferase 2B7 in the glucuronidation of racemic flurbiprofen in the human liver. Drug Metab Dispos. 2007 Jul;35(7):1182-7.
26 Effect of CYP2C9 genetic polymorphism on the metabolism of flurbiprofen in vitro. Drug Dev Ind Pharm. 2015;41(8):1363-7.
27 Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
28 Differential activation of CYP2C9 variants by dapsone. Biochem Pharmacol. 2004 May 15;67(10):1831-41.
29 Aspirin-like drugs can protect human T lymphocytes against benzoquinone cytotoxicity: evidence for a NAD(P)H:quinone reductase-dependent mechanism. Arch Toxicol. 1995;69(10):684-9.
30 Reactive oxygen species are involved in the apoptosis induced by nonsteroidal anti-inflammatory drugs in cultured gastric cells. Eur J Pharmacol. 1999 Nov 3;383(3):331-7.
31 Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen. Oncogene. 2001 Oct 18;20(47):6864-70.
32 Cyclooxygenase-2 expression by nonsteroidal anti-inflammatory drugs in human airway smooth muscle cells: role of peroxisome proliferator-activated receptors. J Immunol. 2003 Jan 15;170(2):1043-51.
33 In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res. 2007 Apr;55(4):318-28.
34 Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner. Mech Ageing Dev. 2008 Dec;129(12):706-13.
35 Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs. Chem Biol Interact. 2009 Mar 16;178(1-3):221-7.
36 Flurbiprofen inhibits androgen productions in rat immature leydig cells. Chem Res Toxicol. 2019 Aug 19;32(8):1504-1514.
37 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer HT29 cells. Arch Biochem Biophys. 2009 Jul 15;487(2):139-45. doi: 10.1016/j.abb.2009.05.017. Epub 2009 Jun 6.
38 Serum protein binding of nonsteroidal antiinflammatory drugs: a comparative study. J Pharmacokinet Biopharm. 1997 Feb;25(1):63-77. doi: 10.1023/a:1025719827072.
39 The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells. Cancer Res. 2007 Dec 1;67(23):11402-10. doi: 10.1158/0008-5472.CAN-07-1792.
40 A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro. Cancer Chemother Pharmacol. 2008 Feb;61(2):203-14. doi: 10.1007/s00280-007-0462-3. Epub 2007 Apr 20.
41 Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs. J Biol Chem. 2002 Oct 11;277(41):38212-21. doi: 10.1074/jbc.M205142200. Epub 2002 Jul 29.
42 Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide. Chem Biol Interact. 2023 Sep 1;382:110644. doi: 10.1016/j.cbi.2023.110644. Epub 2023 Jul 25.
43 NSAID inhibition of prostate cancer cell migration is mediated by Nag-1 Induction via the p38 MAPK-p75(NTR) pathway. Mol Cancer Res. 2010 Dec;8(12):1656-64. doi: 10.1158/1541-7786.MCR-10-0342. Epub 2010 Nov 19.