Details of the Drug Combination

General Information of Drug Combination (ID: DCHENMG)

Drug Combination Name

Ketamine Propofol

Indication

Disease Entry	Status	REF
Trauma	Phase 1	[1]

Component Drugs

Ketamine DMT5HA4

Propofol DMB4OLE

Small molecular drug

2D 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	[9]
------------------------------------------------------------------------------------

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	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[10]
------------------------------------------------------------------------------------

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	[11]
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Increases Expression	[8]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[8]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[12]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[12]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[8]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[13]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[8]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[14]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[15]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[16]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[16]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[8]
Protein S100-A4 (S100A4)	OTLRGFSQ	S10A4_HUMAN	Increases Expression	[8]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[16]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Increases Expression	[8]
TGF-beta receptor type-2 (TGFBR2)	OT3P7GZP	TGFR2_HUMAN	Increases Expression	[8]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[17]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Increases Expression	[14]
Leptin receptor (LEPR)	OT9H7G0C	LEPR_HUMAN	Decreases Expression	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[17]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[17]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[8]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Localization	[17]
Sodium/hydrogen exchanger 6 (SLC9A6)	OT5N47TC	SL9A6_HUMAN	Decreases Expression	[15]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Decreases Response To Substance	[18]
------------------------------------------------------------------------------------


⏷ Show the Full List of 27 DOT(s)

Indication(s) of Propofol

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[5]
Leukemia	N.A.	Approved	[6]
Traumatic brain injury	NA07.Z	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[7]

Propofol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Fatty acid amide hydrolase (FAAH)	TTDP1UC	NOUNIPROTAC	Inhibitor	[21]
------------------------------------------------------------------------------------

Propofol Interacts with 14 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[23]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[24]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[25]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[26]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[23]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[25]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[25]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[22]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[27]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[28]
UDP-glucuronosyltransferase 1A6 (UGT1A6)	DESD26P	UD16_HUMAN	Metabolism	[29]
Oleamide hydrolase 1 (FAAH)	DEUM1EX	FAAH1_HUMAN	Metabolism	[30]
------------------------------------------------------------------------------------


⏷ Show the Full List of 14 DME(s)

Propofol Interacts with 58 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Carbonic anhydrase 1 (CA1)	OTNFBVVQ	CAH1_HUMAN	Decreases Activity	[31]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Decreases Activity	[31]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Activity	[32]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[32]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[32]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[32]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[32]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[32]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[32]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[32]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[32]
Leucine-rich colipase-like protein 1 (LRCOL1)	OTDXBZF8	LRCL1_HUMAN	Decreases Expression	[20]
Glutamate dehydrogenase 1, mitochondrial (GLUD1)	OTXKOCUH	DHE3_HUMAN	Decreases Expression	[33]
Progonadoliberin-1 (GNRH1)	OTH8A44K	GON1_HUMAN	Increases Expression	[34]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Secretion	[35]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[34]
Interleukin-2 receptor subunit alpha (IL2RA)	OT0MWCHG	IL2RA_HUMAN	Decreases Secretion	[36]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[34]
Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2)	OTTLGRGH	GNAI2_HUMAN	Decreases Expression	[20]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Increases Expression	[34]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[37]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[34]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[34]
Small ribosomal subunit protein uS2 (RPSA)	OTJZHEGT	RSSA_HUMAN	Increases Expression	[34]
Matrilysin (MMP7)	OTVT3SEJ	MMP7_HUMAN	Increases Expression	[34]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[33]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[20]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases Expression	[34]
Metalloproteinase inhibitor 2 (TIMP2)	OT8S1RRP	TIMP2_HUMAN	Increases Expression	[34]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[37]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[33]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[33]
Ephrin type-B receptor 2 (EPHB2)	OT8VZ6C5	EPHB2_HUMAN	Increases Expression	[34]
3-oxo-5-alpha-steroid 4-dehydrogenase 2 (SRD5A2)	OTTG0NFD	S5A2_HUMAN	Decreases Expression	[20]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[20]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Increases Expression	[34]
Carbonic anhydrase 5A, mitochondrial (CA5A)	OTP9M7VW	CAH5A_HUMAN	Decreases Expression	[20]
Pigment epithelium-derived factor (SERPINF1)	OTWZH98J	PEDF_HUMAN	Increases Expression	[33]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[20]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[33]
Stromal cell-derived factor 1 (CXCL12)	OT2QX5LL	SDF1_HUMAN	Decreases Expression	[33]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[20]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Decreases Expression	[33]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Decreases Expression	[34]
RNA-binding protein EWS (EWSR1)	OT7SRHV3	EWS_HUMAN	Increases Expression	[34]
Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A (MGAT5)	OTU4DD4G	MGT5A_HUMAN	Increases Expression	[34]
Interleukin-18 (IL18)	OTBB2A8O	IL18_HUMAN	Increases Expression	[34]
Mothers against decapentaplegic homolog 2 (SMAD2)	OTC6VB4K	SMAD2_HUMAN	Decreases Expression	[34]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[33]
Transmembrane channel-like protein 6 (TMC6)	OTKH50J4	TMC6_HUMAN	Increases Expression	[20]
Polycystin-1-like protein 3 (PKD1L3)	OTQMYNOW	PK1L3_HUMAN	Decreases Expression	[20]
Uncharacterized protein C10orf67, mitochondrial (C10ORF67)	OTX24W0H	CJ067_HUMAN	Increases Expression	[20]
Sodium-coupled neutral amino acid transporter 3 (SLC38A3)	OTCHH25G	S38A3_HUMAN	Decreases Expression	[20]
Oxidoreductase HTATIP2 (HTATIP2)	OT9MZ4QO	HTAI2_HUMAN	Increases Expression	[34]
Pinin (PNN)	OT0HXICH	PININ_HUMAN	Decreases Expression	[34]
Protein turtle homolog B (IGSF9B)	OTNOMYYQ	TUTLB_HUMAN	Decreases Expression	[20]
Heparanase (HPSE)	OTPTK5VS	HPSE_HUMAN	Increases Expression	[34]
Mitochondrial pyruvate carrier 1 (MPC1)	OT6DYFUO	MPC1_HUMAN	Decreases Expression	[33]
------------------------------------------------------------------------------------


⏷ Show the Full List of 58 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Retinopathy	DCDT501	N. A.	Phase 4	[38]
Endoscopy	DCW7096	N. A.	Phase 1	[39]
------------------------------------------------------------------------------------

References

1	ClinicalTrials.gov (NCT04291521) Prospective Study of Induction Medications Used in the Trauma RSI
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	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: 5464).
6	Propofol FDA Label
7	Propofol and sedation in patients with coronavirus disease. Am J Emerg Med. 2020 Jun 18;S0735-6757(20)30512-X.
8	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.
9	Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64.
10	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.
11	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.
12	Ketamine hypertension and the renin-angiotensin system. Clin Exp Hypertens A. 1983;5(6):875-83. doi: 10.3109/10641968309081814.
13	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.
14	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.
15	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.
16	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.
17	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.
18	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.
19	Effects of beta-estradiol and propofol on the 4-methylumbelliferone glucuronidation in recombinant human UGT isozymes 1A1, 1A8 and 1A9. Biopharm Drug Dispos. 2004 Nov;25(8):339-44.
20	Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211065972. doi: 10.1177/09603271211065972.
21	Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
22	Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology. 2001 Jan;94(1):110-9.
23	Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
24	Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):211-4.
25	Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
26	Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
27	Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 Jul;37(7):717-24.
28	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.
29	Pharmacokinetics of propofol and extrahepatic UGT1A6 gene expression in anhepatic rats. Pharmacology. 2009;84(4):219-26.
30	Update of TTD: therapeutic target database. Nucleic Acids Res. 2010 Jan;38(Database issue):D787-91.
31	Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols bioorg. Med Chem. 2009 Apr 15;17(8):3207-11.
32	Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes. Environ Toxicol. 2017 Dec;32(12):2440-2454.
33	Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms. Cell Biol Toxicol. 2023 Aug;39(4):1395-1411. doi: 10.1007/s10565-022-09766-6. Epub 2022 Oct 8.
34	The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
35	Propofol withdrawal seizures (or not). Seizure. 2008 Oct;17(7):665-7. doi: 10.1016/j.seizure.2008.03.004. Epub 2008 May 14.
36	Effects of different anaesthetic agents on immune cell function in vitro. Eur J Anaesthesiol. 2005 Aug;22(8):616-23. doi: 10.1017/s0265021505001031.
37	The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function. Br J Anaesth. 2006 Dec;97(6):825-31. doi: 10.1093/bja/ael270. Epub 2006 Oct 9.
38	ClinicalTrials.gov (NCT01955135) Anesthesia for Retinopathy of Prematurity
39	ClinicalTrials.gov (NCT00614159) Ketamine Compared to Propofol for Pediatric GI Endoscopy