General Information of Drug Combination (ID: DC8GLA3)

Drug Combination Name
Ketoprofen Morphine
Indication
Disease Entry Status REF
Pain, Postoperative Phase 4 [1]
Component Drugs Ketoprofen   DMRKXPT Morphine   DMRMS0L
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 Ketoprofen
Disease Entry ICD 11 Status REF
Bursitis N.A. Approved [2]
Dysmenorrhea GA34.3 Approved [2]
Musculoskeletal pain MG30 Approved [3]
Pain MG30-MG3Z Phase 3 [4]
Migraine 8A80 Phase 2 [5]
Osteoarthritis FA00-FA05 Phase 1 [5]
Ketoprofen 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 Inhibitor [12]
------------------------------------------------------------------------------------
Ketoprofen Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [13]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [14]
------------------------------------------------------------------------------------
Ketoprofen Interacts with 16 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Tumor necrosis factor (TNF) OT4IE164 TNFA_HUMAN Increases ADR [15]
Glutathione reductase, mitochondrial (GSR) OTM2TUYM GSHR_HUMAN Increases ADR [15]
Solute carrier family 22 member 1 (SLC22A1) OT7817I4 S22A1_HUMAN Decreases Activity [16]
Solute carrier family 22 member 6 (SLC22A6) OTKRCBVM S22A6_HUMAN Decreases Activity [16]
Organic anion transporter 7 (SLC22A9) OTO4BJCC S22A9_HUMAN Decreases Activity [16]
Solute carrier family 22 member 11 (SLC22A11) OTAJLNJZ S22AB_HUMAN Decreases Activity [16]
Solute carrier family 22 member 7 (SLC22A7) OTKTNH1W S22A7_HUMAN Decreases Activity [16]
Tumor necrosis factor receptor superfamily member 16 (NGFR) OTPKSM49 TNR16_HUMAN Increases Expression [17]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1) OTVVI3UI DQB1_HUMAN Affects Expression [18]
Albumin (ALB) OTVMM513 ALBU_HUMAN Affects Binding [19]
L-selectin (SELL) OT6RAJZR LYAM1_HUMAN Decreases Expression [20]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1) OT7OG7Y2 DPA1_HUMAN Affects Expression [18]
Glutamate--cysteine ligase catalytic subunit (GCLC) OTESDI4D GSH1_HUMAN Increases Expression [21]
Glutamate--cysteine ligase regulatory subunit (GCLM) OT6CP234 GSH0_HUMAN Increases Expression [21]
Cytochrome P450 4A11 (CYP4A11) OTPU5J0S CP4AB_HUMAN Affects Activity [22]
Dehydrogenase/reductase SDR family member 11 (DHRS11) OTU3J0ZL DHR11_HUMAN Decreases Activity [23]
------------------------------------------------------------------------------------
⏷ Show the Full List of 16 DOT(s)
Indication(s) of Morphine
Disease Entry ICD 11 Status REF
Advanced cancer 2A00-2F9Z Approved [6]
Chronic pain MG30 Approved [7]
Pain MG30-MG3Z Approved [6]
Diarrhea ME05.1 Investigative [6]
Morphine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Opioid receptor mu (MOP) TTKWM86 OPRM_HUMAN Modulator [27]
------------------------------------------------------------------------------------
Morphine Interacts with 2 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [28]
Multidrug resistance-associated protein 3 (ABCC3) DTQ3ZHF MRP3_HUMAN Substrate [29]
------------------------------------------------------------------------------------
Morphine Interacts with 6 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [30]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [31]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [32]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [33]
UDP-glucuronosyltransferase 2B7 (UGT2B7) DEB3CV1 UD2B7_HUMAN Metabolism [34]
UDP-glucuronosyltransferase 1A3 (UGT1A3) DEF2WXN UD13_HUMAN Metabolism [35]
------------------------------------------------------------------------------------
⏷ Show the Full List of 6 DME(s)
Morphine Interacts with 47 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 2D6 (CYP2D6) OTZJC802 CP2D6_HUMAN Affects Chemical Synthesis [36]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Response [37]
Mu-type opioid receptor (OPRM1) OT16AAT8 OPRM_HUMAN Increases Response [37]
Toll-like receptor 4 (TLR4) OTP7ML3S TLR4_HUMAN Affects Binding [38]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [39]
LIM homeobox transcription factor 1-beta (LMX1B) OTM8145D LMX1B_HUMAN Increases Expression [40]
Krueppel-like factor 7 (KLF7) OTS3YVA0 KLF7_HUMAN Increases Expression [41]
Protein c-Fos (FOS) OTJBUVWS FOS_HUMAN Increases Expression [42]
C-reactive protein (CRP) OT0RFT8F CRP_HUMAN Increases Expression [43]
Apolipoprotein B-100 (APOB) OTH0UOCZ APOB_HUMAN Increases Expression [43]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [44]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [40]
Interleukin-4 (IL4) OTOXBWAU IL4_HUMAN Increases Expression [45]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases Secretion [44]
Coagulation factor VII (F7) OTGNJ97M FA7_HUMAN Increases Expression [43]
Fibroblast growth factor 2 (FGF2) OT7YUJ9F FGF2_HUMAN Decreases Secretion [44]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [46]
C-C motif chemokine 5 (CCL5) OTSCA5CK CCL5_HUMAN Decreases Expression [47]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Increases Expression [42]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Increases Phosphorylation [45]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Increases Phosphorylation [45]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Expression [48]
Kappa-type opioid receptor (OPRK1) OTXCZF4L OPRK_HUMAN Increases Activity [49]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [46]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [39]
Interleukin-2 (IL2) OTGI4NSA IL2_HUMAN Decreases Expression [45]
Eukaryotic translation initiation factor 5A-1 (EIF5A) OTQ8DJX5 IF5A1_HUMAN Increases Expression [40]
C-C motif chemokine 8 (CCL8) OTCTWYN8 CCL8_HUMAN Increases Secretion [44]
Cytochrome c (CYCS) OTBFALJD CYC_HUMAN Increases Secretion [39]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Increases Phosphorylation [42]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [46]
Beclin-1 (BECN1) OT4X293M BECN1_HUMAN Increases Expression [50]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Decreases Expression [48]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [51]
DNA damage-binding protein 2 (DDB2) OTO8HVVB DDB2_HUMAN Increases Expression [40]
Ninjurin-1 (NINJ1) OTLRZ1EU NINJ1_HUMAN Increases Expression [40]
Bcl-2-binding component 3, isoforms 3/4 (BBC3) OTUAXDAY BBC3B_HUMAN Increases Expression [40]
Acetylcholinesterase (ACHE) OT2H8HG6 ACES_HUMAN Increases Chemical Synthesis [52]
Interleukin-1 receptor antagonist protein (IL1RN) OT308CBE IL1RA_HUMAN Affects Response To Substance [53]
Protein kinase C alpha type (PRKCA) OT5UWNRD KPCA_HUMAN Increases ADR [15]
Beta-arrestin-2 (ARRB2) OTAEJZCI ARRB2_HUMAN Affects Response To Substance [54]
Cocaine esterase (CES2) OTC647SQ EST2_HUMAN Increases Chemical Synthesis [55]
Signal transducer and activator of transcription 6 (STAT6) OTCKMP49 STAT6_HUMAN Affects Response To Substance [54]
Transcription factor Jun (JUN) OTCYBO6X JUN_HUMAN Increases ADR [15]
Mitogen-activated protein kinase 8 (MAPK8) OTEREYS5 MK08_HUMAN Increases ADR [15]
Platelet-derived growth factor subunit B (PDGFB) OTMFMFC3 PDGFB_HUMAN Decreases Response To Substance [56]
Cholinesterase (BCHE) OTOH3WQ9 CHLE_HUMAN Increases Chemical Synthesis [52]
------------------------------------------------------------------------------------
⏷ Show the Full List of 47 DOT(s)

References

1 ClinicalTrials.gov (NCT02248493) Intravenous Paracetamol for Postoperative Pain
2 Ketoprofen FDA Label
3 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: 4795).
4 Ketoprofen-induced cyclooxygenase inhibition in renal medulla and platelets of rats treated with caffeine. Pharmacology. 2001;63(4):234-9.
5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6 Morphine FDA Label
7 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
8 In vitro inhibitory effects of non-steroidal antiinflammatory drugs on UDP-glucuronosyltransferase 1A1-catalysed estradiol 3beta-glucuronidation in human liver microsomes. Biopharm Drug Dispos. 2005 Jan;26(1):35-9.
9 Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J Pharmacol Exp Ther. 1993 Jan;264(1):475-9.
10 Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
11 Carboxyl nonsteroidal anti-inflammatory drugs are efficiently glucuronidated by microsomes of the human gastrointestinal tract. Biochim Biophys Acta. 2004 Nov 18;1675(1-3):120-9. doi: 10.1016/j.bbagen.2004.08.013.
12 Probing the skin permeation of fish oil/EPA and ketoprofen-3. Effects on epidermal COX-2 and LOX. Prostaglandins Leukot Essent Fatty Acids. 2007 Jun;76(6):357-62.
13 Association between the UGT1A1*28 allele and hyperbilirubinemia in HIV-positive patients receiving atazanavir: a meta-analysis. Biosci Rep. 2019 May 2;39(5). pii: BSR20182105.
14 Clinical pharmacokinetics of ketoprofen enantiomers in wild type of Cyp 2c8 and Cyp 2c9 patients with rheumatoid arthritis. Eur J Drug Metab Pharmacokinet. 2011 Sep;36(3):167-73.
15 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.
16 Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther. 2002 Nov;303(2):534-9.
17 The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. Cancer Res. 2007 Apr 1;67(7):3254-62.
18 Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
19 A protein-coated magnetic beads as a tool for the rapid drug-protein binding study. J Pharm Biomed Anal. 2010 Jul 8;52(3):420-4. doi: 10.1016/j.jpba.2009.06.023. Epub 2009 Jun 18.
20 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.
21 Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Free Radic Biol Med. 2002 Apr 1;32(7):650-62. doi: 10.1016/s0891-5849(02)00755-4.
22 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.
23 Rabbit dehydrogenase/reductase SDR family member 11 (DHRS11): Its identity with acetohexamide reductase with broad substrate specificity and inhibitor sensitivity, different from human DHRS11. Chem Biol Interact. 2019 May 25;305:12-20. doi: 10.1016/j.cbi.2019.03.026. Epub 2019 Mar 26.
24 Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics. 2000 Nov;10(8):679-85. doi: 10.1097/00008571-200011000-00002.
25 Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos. 2003 Sep;31(9):1086-9. doi: 10.1124/dmd.31.9.1086.
26 Inhibition of NF-B by opioids in T cells. J Immunol. 2013 Nov 1;191(9):4640-7. doi: 10.4049/jimmunol.1300320. Epub 2013 Sep 25.
27 Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord.J Pharmacol Exp Ther.2005 Sep;314(3):1101-8.
28 Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand. 2005 Aug;49(7):902-8.
29 Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
30 Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4. Biol Pharm Bull. 2005 Oct;28(10):2026-7.
31 Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008 Apr;36(4):688-94.
32 Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther. 2004 Feb;308(2):547-54.
33 In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005 May;33(5):689-95.
34 Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos. 2010 Apr;38(4):545-53.
35 Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos. 1998 Jun;26(6):507-12.
36 Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004 Dec 30;351(27):2827-31. doi: 10.1056/NEJMoa041888.
37 Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66.
38 Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience. 2010 May 19;167(3):880-93. doi: 10.1016/j.neuroscience.2010.02.011. Epub 2010 Feb 21.
39 Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. FEBS J. 2009 Apr;276(7):2022-36. doi: 10.1111/j.1742-4658.2009.06938.x.
40 Morphine induces DNA damage and P53 activation in CD3+ T cells. Biochim Biophys Acta. 2009 Aug;1790(8):793-9. doi: 10.1016/j.bbagen.2009.04.011. Epub 2009 May 3.
41 Identification of opioid-regulated genes in human lymphocytic cells by differential display: upregulation of Krppel-like factor 7 by morphine. Exp Cell Res. 2003 Dec 10;291(2):340-51. doi: 10.1016/s0014-4827(03)00408-7.
42 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.
43 Effect of opium addiction on new and traditional cardiovascular risk factors: do duration of addiction and route of administration matter?. Lipids Health Dis. 2008 Nov 3;7:42. doi: 10.1186/1476-511X-7-42.
44 Morphine treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: impact on inflammation and oxidative stress in the central nervous system. J Cell Biochem. 2010 Jul 1;110(4):834-45. doi: 10.1002/jcb.22592.
45 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.
46 Morphine promotes apoptosis in Jurkat cells. J Leukoc Biol. 1999 Oct;66(4):650-8. doi: 10.1002/jlb.66.4.650.
47 Morphine inhibits human microglial cell production of, and migration towards, RANTES. J Psychopharmacol. 2000;14(3):238-43. doi: 10.1177/026988110001400307.
48 beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways. Neoplasma. 2009;56(2):108-13. doi: 10.4149/neo_2009_02_108.
49 In vivo and in vitro evaluation of novel -opioid receptor agonist compounds. Eur J Pharmacol. 2015 Nov 15;767:193-200. doi: 10.1016/j.ejphar.2015.10.025. Epub 2015 Oct 20.
50 Morphine induces Beclin 1- and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus. Autophagy. 2010 Apr;6(3):386-94. doi: 10.4161/auto.6.3.11289. Epub 2010 Apr 25.
51 Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology. 2009 Feb 4;256(1-2):83-91. doi: 10.1016/j.tox.2008.11.015. Epub 2008 Nov 25.
52 Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine. Chem Biol Interact. 2018 Sep 25;293:107-114.
53 A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004 Aug 18;24(33):7353-65. doi: 10.1523/JNEUROSCI.1850-04.2004.
54 Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5(5):324-36. doi: 10.1038/sj.tpj.6500327.
55 Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther. 1996 Nov;279(2):713-7.
56 A growth factor attenuates HIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse cases. PLoS One. 2011 Mar 24;6(3):e18116. doi: 10.1371/journal.pone.0018116.