Details of the Drug Combination

General Information of Drug Combination (ID: DCMUQ47)

• Drug Combination Name: Ketamine + Ondansetron
• Indication: Trigeminal Neuralgia; Status: Phase 4 [1]
• Component Drugs:
  Ketamine (DMT5HA4): Small molecular drug
  Ondansetron (DMOTQ1I): Small molecular drug

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	[8]

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]

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]

Indication(s) of Ondansetron

Disease Entry	ICD 11	Status	REF
Chemotherapy-induced nausea	MD90	Approved	[5]
Malignant glioma	2A00.0	Approved	[6]
Nausea	MD90	Approved	[6]
Vomiting	MD90	Approved	[6]
Alcohol dependence	6C40.2	Phase 2	[5]
Gastroenteritis	N.A.	Investigative	[6]

Ondansetron Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 3 receptor (5HT3R)	TTNXLKE	NOUNIPROTAC	Agonist	[18]

Ondansetron Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]

Ondansetron Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[21]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[22]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[23]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[24]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[23]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[25]

Ondansetron Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[26]

References

• [1] ClinicalTrials.gov (NCT03152955) Postoperative Analgesia in Patients With Microvascular Decompression
• [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: 2290).
• [6] Ondansetron FDA Label
• [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] Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial. Eur J Gastroenterol Hepatol. 1998 Oct;10(10):865-70.
• [19] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [20] The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999 Apr;65(4):377-81.
• [21] Effects of serotonin-3 receptor antagonists on cytochrome P450 activities in human liver microsomes. Biol Pharm Bull. 2006 Sep;29(9):1931-5.
• [22] Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit. 2005 Oct;11(10):RA322-8.
• [23] Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab Dispos. 1995 Nov;23(11):1225-30.
• [24] Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. Drug Metab Dispos. 1996 May;24(5):602-9.
• [25] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [26] Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-B downregulation. Cell Biol Toxicol. 2023 Jun;39(3):1119-1135. doi: 10.1007/s10565-021-09667-0. Epub 2021 Oct 15.