Details of the Drug Combination

General Information of Drug Combination (ID: DCMABAL)

• Drug Combination Name: Ketamine + Esketamine
• Indication: Major Depressive Disorder; Status: Phase 4 [1]
• Component Drugs:
  Ketamine (DMT5HA4): Small molecular drug
  Esketamine (DMVU687): N.A.

Molecular Interaction Atlas of This Drug Combination

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	[7]

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	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[8]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[8]

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	[9]
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Increases Expression	[6]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[6]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[10]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[10]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[6]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[11]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[6]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[12]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[14]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[14]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[6]
Protein S100-A4 (S100A4)	OTLRGFSQ	S10A4_HUMAN	Increases Expression	[6]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[14]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Increases Expression	[6]
TGF-beta receptor type-2 (TGFBR2)	OT3P7GZP	TGFR2_HUMAN	Increases Expression	[6]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[15]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Increases Expression	[12]
Leptin receptor (LEPR)	OT9H7G0C	LEPR_HUMAN	Decreases Expression	[14]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[15]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[15]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[6]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Localization	[15]
Sodium/hydrogen exchanger 6 (SLC9A6)	OT5N47TC	SL9A6_HUMAN	Decreases Expression	[13]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Decreases Response To Substance	[16]

Indication(s) of Esketamine

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Phase 3	[5]

Esketamine 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	[5]

Esketamine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[8]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Treatment Resistant Depression	DCN4IIW	N. A.	Phase 1	[18]

References

• [1] ClinicalTrials.gov (NCT05450432) Long-Term Maintenance With Ketamine and Esketamine for Reduction of Suicide in High-Risk Patients With Depression
• [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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] 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.
• [7] Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64.
• [8] 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.
• [9] 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.
• [10] Ketamine hypertension and the renin-angiotensin system. Clin Exp Hypertens A. 1983;5(6):875-83. doi: 10.3109/10641968309081814.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Metabolism and metabolomics of ketamine: a toxicological approach. Forensic Sci Res. 2017 Feb 20;2(1):2-10.
• [18] ClinicalTrials.gov (NCT04480918) University of Iowa Interventional Psychiatry Service Patient Registry