Details of the Drug Combination

General Information of Drug Combination (ID: DC0BTFI)

Drug Combination Name
Ketamine Morphine
Indication
Disease Entry Status REF
Acute Pain Phase 1 [1]
Component Drugs Ketamine   DMT5HA4 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 Ketamine
Disease Entry ICD 11 Status REF
Anaesthesia 9A78.6 Approved [2]
Anxiety N.A. Approved [3]
Bipolar disorder 6A60 Approved [3]
Depression 6A70-6A7Z Approved [3]
Traumatic brain injury NA07.Z Approved [3]
Coronavirus Disease 2019 (COVID-19) 1D6Y Phase 2 [4]
Chronic pain MG30 Investigative [3]
Ketamine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
N-methyl-D-aspartate receptor (NMDAR) TT9IK2Z NOUNIPROTAC Antagonist [8]
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Ketamine Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [9]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [9]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [9]
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Ketamine Interacts with 27 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Decreases Expression [10]
Zinc finger protein SNAI2 (SNAI2) OT7Y8EJ2 SNAI2_HUMAN Increases Expression [7]
Zinc finger protein SNAI1 (SNAI1) OTDPYAMC SNAI1_HUMAN Increases Expression [7]
Renin (REN) OT52GZR2 RENI_HUMAN Increases Expression [11]
Angiotensinogen (AGT) OTBZLYR3 ANGT_HUMAN Decreases Expression [11]
Transforming growth factor beta-1 proprotein (TGFB1) OTV5XHVH TGFB1_HUMAN Increases Expression [7]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Increases Secretion [12]
Fibronectin (FN1) OTB5ZN4Q FINC_HUMAN Increases Expression [7]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [13]
Amyloid-beta precursor protein (APP) OTKFD7R4 A4_HUMAN Increases Expression [14]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [15]
Endoplasmic reticulum chaperone BiP (HSPA5) OTFUIRAO BIP_HUMAN Increases Expression [15]
Cadherin-1 (CDH1) OTFJMXPM CADH1_HUMAN Decreases Expression [7]
Protein S100-A4 (S100A4) OTLRGFSQ S10A4_HUMAN Increases Expression [7]
DNA damage-inducible transcript 3 protein (DDIT3) OTI8YKKE DDIT3_HUMAN Increases Expression [15]
TGF-beta receptor type-1 (TGFBR1) OT40S1SJ TGFR1_HUMAN Increases Expression [7]
TGF-beta receptor type-2 (TGFBR2) OT3P7GZP TGFR2_HUMAN Increases Expression [7]
Leptin (LEP) OT5Q7ODW LEP_HUMAN Decreases Expression [15]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [16]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Increases Expression [13]
Leptin receptor (LEPR) OT9H7G0C LEPR_HUMAN Decreases Expression [15]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [16]
Caspase-6 (CASP6) OTXLD3EC CASP6_HUMAN Increases Activity [16]
Actin, aortic smooth muscle (ACTA2) OTEDLG8E ACTA_HUMAN Increases Expression [7]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Affects Localization [16]
Sodium/hydrogen exchanger 6 (SLC9A6) OT5N47TC SL9A6_HUMAN Decreases Expression [14]
Apolipoprotein E (APOE) OTFOWL2H APOE_HUMAN Decreases Response To Substance [17]
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⏷ Show the Full List of 27 DOT(s)
Indication(s) of Morphine
Disease Entry ICD 11 Status REF
Advanced cancer 2A00-2F9Z Approved [5]
Chronic pain MG30 Approved [6]
Pain MG30-MG3Z Approved [5]
Diarrhea ME05.1 Investigative [5]
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 [21]
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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 [22]
Multidrug resistance-associated protein 3 (ABCC3) DTQ3ZHF MRP3_HUMAN Substrate [23]
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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 [24]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [25]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [26]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [27]
UDP-glucuronosyltransferase 2B7 (UGT2B7) DEB3CV1 UD2B7_HUMAN Metabolism [28]
UDP-glucuronosyltransferase 1A3 (UGT1A3) DEF2WXN UD13_HUMAN Metabolism [29]
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⏷ 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 [30]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Response [31]
Mu-type opioid receptor (OPRM1) OT16AAT8 OPRM_HUMAN Increases Response [31]
Toll-like receptor 4 (TLR4) OTP7ML3S TLR4_HUMAN Affects Binding [32]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [33]
LIM homeobox transcription factor 1-beta (LMX1B) OTM8145D LMX1B_HUMAN Increases Expression [34]
Krueppel-like factor 7 (KLF7) OTS3YVA0 KLF7_HUMAN Increases Expression [35]
Protein c-Fos (FOS) OTJBUVWS FOS_HUMAN Increases Expression [36]
C-reactive protein (CRP) OT0RFT8F CRP_HUMAN Increases Expression [37]
Apolipoprotein B-100 (APOB) OTH0UOCZ APOB_HUMAN Increases Expression [37]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [38]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [34]
Interleukin-4 (IL4) OTOXBWAU IL4_HUMAN Increases Expression [39]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases Secretion [38]
Coagulation factor VII (F7) OTGNJ97M FA7_HUMAN Increases Expression [37]
Fibroblast growth factor 2 (FGF2) OT7YUJ9F FGF2_HUMAN Decreases Secretion [38]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [40]
C-C motif chemokine 5 (CCL5) OTSCA5CK CCL5_HUMAN Decreases Expression [41]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Increases Expression [36]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Increases Phosphorylation [39]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Increases Phosphorylation [39]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Expression [42]
Kappa-type opioid receptor (OPRK1) OTXCZF4L OPRK_HUMAN Increases Activity [43]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [40]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [33]
Interleukin-2 (IL2) OTGI4NSA IL2_HUMAN Decreases Expression [39]
Eukaryotic translation initiation factor 5A-1 (EIF5A) OTQ8DJX5 IF5A1_HUMAN Increases Expression [34]
C-C motif chemokine 8 (CCL8) OTCTWYN8 CCL8_HUMAN Increases Secretion [38]
Cytochrome c (CYCS) OTBFALJD CYC_HUMAN Increases Secretion [33]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Increases Phosphorylation [36]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [40]
Beclin-1 (BECN1) OT4X293M BECN1_HUMAN Increases Expression [44]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Decreases Expression [42]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [45]
DNA damage-binding protein 2 (DDB2) OTO8HVVB DDB2_HUMAN Increases Expression [34]
Ninjurin-1 (NINJ1) OTLRZ1EU NINJ1_HUMAN Increases Expression [34]
Bcl-2-binding component 3, isoforms 3/4 (BBC3) OTUAXDAY BBC3B_HUMAN Increases Expression [34]
Acetylcholinesterase (ACHE) OT2H8HG6 ACES_HUMAN Increases Chemical Synthesis [46]
Interleukin-1 receptor antagonist protein (IL1RN) OT308CBE IL1RA_HUMAN Affects Response To Substance [47]
Protein kinase C alpha type (PRKCA) OT5UWNRD KPCA_HUMAN Increases ADR [48]
Beta-arrestin-2 (ARRB2) OTAEJZCI ARRB2_HUMAN Affects Response To Substance [49]
Cocaine esterase (CES2) OTC647SQ EST2_HUMAN Increases Chemical Synthesis [50]
Signal transducer and activator of transcription 6 (STAT6) OTCKMP49 STAT6_HUMAN Affects Response To Substance [49]
Transcription factor Jun (JUN) OTCYBO6X JUN_HUMAN Increases ADR [48]
Mitogen-activated protein kinase 8 (MAPK8) OTEREYS5 MK08_HUMAN Increases ADR [48]
Platelet-derived growth factor subunit B (PDGFB) OTMFMFC3 PDGFB_HUMAN Decreases Response To Substance [51]
Cholinesterase (BCHE) OTOH3WQ9 CHLE_HUMAN Increases Chemical Synthesis [46]
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⏷ Show the Full List of 47 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Progressive Infantile Idiopathic Scoliosis DCTFQ3X N. A. Phase 2 [52]
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References

1 ClinicalTrials.gov (NCT01900847) Ketamine and Morphine Versus Morphine Alone for the Treatment of Acute Pain in the Emergency Department
2 FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 076092.
3 Ketamine FDA Label
4 ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
5 Morphine FDA Label
6 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
7 Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-1. Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F961-F972. doi: 10.1152/ajprenal.00686.2016. Epub 2017 Mar 22.
8 Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64.
9 Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002 Jul;30(7):853-8.
10 Cytoskeleton interruption in human hepatoma HepG2 cells induced by ketamine occurs possibly through suppression of calcium mobilization and mitochondrial function. Drug Metab Dispos. 2009 Jan;37(1):24-31.
11 Ketamine hypertension and the renin-angiotensin system. Clin Exp Hypertens A. 1983;5(6):875-83. doi: 10.3109/10641968309081814.
12 Cellular consequences triggered by ketamine on exposure to human glioblastoma epithelial (LN-229) cells. J Biochem Mol Toxicol. 2023 Dec;37(12):e23484. doi: 10.1002/jbt.23484. Epub 2023 Jul 29.
13 Ketamine cystitis as a mimic of carcinoma in situ. Histopathology. 2009 Dec;55(6):705-8. doi: 10.1111/j.1365-2559.2009.03437.x.
14 Ketamine promotes the amyloidogenic pathway by regulating endosomal pH. Toxicology. 2022 Apr 15;471:153163. doi: 10.1016/j.tox.2022.153163. Epub 2022 Apr 1.
15 Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway. Toxicol In Vitro. 2023 Jun;89:105581. doi: 10.1016/j.tiv.2023.105581. Epub 2023 Mar 11.
16 Apoptotic insults to human HepG2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondria-caspase protease pathway. Br J Anaesth. 2009 Jan;102(1):80-9. doi: 10.1093/bja/aen322. Epub 2008 Nov 9.
17 The apolipoprotein E epsilon 4 allele is associated with blunting of ketamine-induced psychosis in schizophrenia. A preliminary report. Neuropsychopharmacology. 1998 Nov;19(5):445-8. doi: 10.1016/S0893-133X(98)00031-1.
18 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.
19 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.
20 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.
21 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.
22 Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand. 2005 Aug;49(7):902-8.
23 Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
24 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.
25 Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008 Apr;36(4):688-94.
26 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.
27 In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005 May;33(5):689-95.
28 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.
29 Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos. 1998 Jun;26(6):507-12.
30 Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004 Dec 30;351(27):2827-31. doi: 10.1056/NEJMoa041888.
31 Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66.
32 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.
33 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.
34 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.
35 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.
36 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.
37 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.
38 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.
39 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.
40 Morphine promotes apoptosis in Jurkat cells. J Leukoc Biol. 1999 Oct;66(4):650-8. doi: 10.1002/jlb.66.4.650.
41 Morphine inhibits human microglial cell production of, and migration towards, RANTES. J Psychopharmacol. 2000;14(3):238-43. doi: 10.1177/026988110001400307.
42 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.
43 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.
44 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.
45 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.
46 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.
47 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.
48 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.
49 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.
50 Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther. 1996 Nov;279(2):713-7.
51 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.
52 ClinicalTrials.gov (NCT02571491) Comparison of the Efficacy of Ketamine in Pediatric Patients With Idiopathic Scoliosis After Surgery