Details of the Drug Combination

General Information of Drug Combination (ID: DC2JFQ5)

• Drug Combination Name: Edivoxetine + Fluoxetine
• Indication: Major Depressive Disorder; Status: Phase 1 [1]
• Component Drugs:
  Edivoxetine (DMFTTMK): Small molecular drug
  Fluoxetine (DM3PD2C): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Edivoxetine

Disease Entry	ICD 11	Status	REF
Major depressive disorder	6A70.3	Phase 3	[2]
Pediatric attention deficit hyperactivity disorder	6A05	Phase 3	[2]

Indication(s) of Fluoxetine

Disease Entry	ICD 11	Status	REF
Bipolar depression	N.A.	Approved	[3]
Bulimia nervosa	6B81	Approved	[3]
Depression	6A70-6A7Z	Approved	[4]
Intracerebral hemorrhage	N.A.	Approved	[3]
Major depressive disorder	6A70.3	Approved	[3]
Obsessive compulsive disorder	6B20	Approved	[3]
Panic disorder	6B01	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[5]

Fluoxetine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Modulator	[9]

Fluoxetine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Fluoxetine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[16]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[17]

Fluoxetine Interacts with 66 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Decreases Response To Substance	[18]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[6]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[6]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[6]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[6]
AP-1 complex subunit sigma-1A (AP1S1)	OTQ2H8DN	AP1S1_HUMAN	Decreases Expression	[6]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[6]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[6]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[6]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[6]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[19]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Affects Binding	[20]
Protein EVI2A (EVI2A)	OTR8RUXQ	EVI2A_HUMAN	Increases Expression	[7]
Inactive phospholipase C-like protein 1 (PLCL1)	OTJL2C79	PLCL1_HUMAN	Increases Expression	[7]
Cyclin-G2 (CCNG2)	OTII38K2	CCNG2_HUMAN	Increases Expression	[7]
Kelch-like protein 24 (KLHL24)	OTWZSX5C	KLH24_HUMAN	Increases Expression	[7]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[21]
Ras-related protein Rab-7L1 (RAB29)	OTDZT6LP	RAB7L_HUMAN	Increases Expression	[8]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[8]
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)	OTI71MUJ	ACSL4_HUMAN	Increases Expression	[8]
Lathosterol oxidase (SC5D)	OT41KMW4	SC5D_HUMAN	Increases Expression	[8]
Membrane protein BRI3 (BRI3)	OT1RWIH7	BRI3_HUMAN	Increases Expression	[8]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Decreases Expression	[8]
Fatty acid CoA ligase Acsl3 (ACSL3)	OT3MWER1	ACSL3_HUMAN	Increases Expression	[8]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Expression	[22]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Phosphorylation	[22]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Decreases Expression	[22]
Fatty acid-binding protein, heart (FABP3)	OT562DA1	FABPH_HUMAN	Increases Expression	[8]
Fructose-bisphosphate aldolase C (ALDOC)	OTEC13I5	ALDOC_HUMAN	Increases Expression	[8]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[23]
Transcobalamin-2 (TCN2)	OT41D0L3	TCO2_HUMAN	Increases Expression	[8]
Potassium voltage-gated channel subfamily A member 3 (KCNA3)	OTXSP3AA	KCNA3_HUMAN	Decreases Activity	[24]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[22]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[22]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[25]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[22]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[8]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Affects Expression	[26]
3-keto-steroid reductase/17-beta-hydroxysteroid dehydrogenase 7 (HSD17B7)	OTV7VOV3	DHB7_HUMAN	Increases Expression	[8]
Cyclin-dependent kinases regulatory subunit 1 (CKS1B)	OTNUPLUJ	CKS1_HUMAN	Decreases Expression	[26]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[21]
Isopentenyl-diphosphate Delta-isomerase 1 (IDI1)	OTGM06VJ	IDI1_HUMAN	Increases Expression	[8]
Phosphatidate phosphatase LPIN1 (LPIN1)	OTQ75KF2	LPIN1_HUMAN	Increases Expression	[8]
3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase (EBP)	OTSMGKXQ	EBP_HUMAN	Increases Expression	[8]
Mitochondrial fission regulator 1 (MTFR1)	OTLB1VFT	MTFR1_HUMAN	Increases Expression	[8]
Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL)	OTK3EJFD	NSDHL_HUMAN	Increases Expression	[8]
LON peptidase N-terminal domain and RING finger protein 1 (LONRF1)	OT0S9MFX	LONF1_HUMAN	Increases Expression	[8]
Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (PIP4P1)	OT991XS0	PP4P1_HUMAN	Increases Expression	[8]
Osteopetrosis-associated transmembrane protein 1 (OSTM1)	OTKNJDH7	OSTM1_HUMAN	Increases Expression	[8]
Polypeptide N-acetylgalactosaminyltransferase 11 (GALNT11)	OTANT9E6	GLT11_HUMAN	Increases Expression	[8]
RCC1 and BTB domain-containing protein 1 (RCBTB1)	OTAYELI8	RCBT1_HUMAN	Increases Expression	[8]
Folliculin (FLCN)	OTVM78XM	FLCN_HUMAN	Increases Expression	[8]
Folliculin-interacting protein 1 (FNIP1)	OTB1CC41	FNIP1_HUMAN	Increases Expression	[8]
StAR-related lipid transfer protein 4 (STARD4)	OTPQ0BFY	STAR4_HUMAN	Increases Expression	[8]
Sodium-coupled neutral amino acid symporter 2 (SLC38A2)	OTALABSK	S38A2_HUMAN	Increases Expression	[8]
Ethanolamine-phosphate cytidylyltransferase (PCYT2)	OTT8TAEA	PCY2_HUMAN	Increases Expression	[8]
Sialidase-1 (NEU1)	OTH9BY8Y	NEUR1_HUMAN	Increases Expression	[8]
17-beta-hydroxysteroid dehydrogenase 14 (HSD17B14)	OT0ETO72	DHB14_HUMAN	Increases Expression	[8]
Ethanolaminephosphotransferase 1 (SELENOI)	OTX2A47A	EPT1_HUMAN	Increases Expression	[8]
Acetyl-coenzyme A synthetase, cytoplasmic (ACSS2)	OTB1FZJU	ACSA_HUMAN	Increases Expression	[8]
1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3)	OTR4990X	PLPL3_HUMAN	Increases Expression	[8]
Maspardin (SPG21)	OTMKJSYS	SPG21_HUMAN	Increases Expression	[8]
7-dehydrocholesterol reductase (DHCR7)	OTLILBUI	DHCR7_HUMAN	Increases Expression	[8]
Potassium voltage-gated channel subfamily D member 3 (KCND3)	OTRPIH7J	KCND3_HUMAN	Decreases Activity	[27]
Ergosterol biosynthetic protein 28 homolog (ERG28)	OT2KAOBA	ERG28_HUMAN	Increases Expression	[8]
5-hydroxytryptamine receptor 1A (HTR1A)	OT38K9MK	5HT1A_HUMAN	Increases Response To Substance	[28]

References

• [1] ClinicalTrials.gov (NCT01243957) A Study to Measure if There is Any Difference in How the Body Breaks Down or Inactivates Either Fluoxetine or LY2216684 When Both of These Medicines Are Given Together.
• [2] ClinicalTrials.gov (NCT01370499) A Study of LY2216684 in Patients With Major Depression Disorder. U.S. National Institutes of Health.
• [3] Fluoxetine FDA Label
• [4] 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: 203).
• [5] Fluoxetine to Reduce Intubation and Death After COVID19 Infection
• [6] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [7] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [8] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [10] Fluoxetine and reversal of multidrug resistance. Cancer Lett. 2006 Jun 18;237(2):180-7.
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• [13] (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug Metab Dispos. 2000 Oct;28(10):1187-91.
• [14] Antidepressant drugs in the elderly--role of the cytochrome P450 2D6. World J Biol Psychiatry. 2003 Apr;4(2):74-80.
• [15] Binding of CYP2C9 with diverse drugs and its implications for metabolic mechanism. Med Chem. 2009 May;5(3):263-70.
• [16] Molecular characterization of CYP2B6 substrates. Curr Drug Metab. 2008 Jun;9(5):363-73.
• [17] Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver microsomes. Acta Pharmacol Sin. 2001 Jan;22(1):85-90.
• [18] Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline. Int J Neuropsychopharmacol. 2003 Dec;6(4):339-46. doi: 10.1017/S1461145703003663.
• [19] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [20] Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulatio... Mol Pharmacol. 2008 Mar;73(3):748-57.
• [21] Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells. Neurosci Lett. 2006 Mar 13;395(3):185-90. doi: 10.1016/j.neulet.2005.10.096. Epub 2005 Dec 1.
• [22] Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells. Cancer Biol Ther. 2008 Oct;7(10):1685-93. doi: 10.4161/cbt.7.10.6664. Epub 2008 Oct 22.
• [23] 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.
• [24] A cell-based Rb(+)-flux assay of the Kv1.3 potassium channel. Assay Drug Dev Technol. 2007 Jun;5(3):373-80. doi: 10.1089/adt.2006.004.
• [25] Downregulation of glucose-6-phosphatase expression contributes to fluoxetine-induced hepatic steatosis. J Appl Toxicol. 2021 Aug;41(8):1232-1240. doi: 10.1002/jat.4109. Epub 2020 Nov 12.
• [26] Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1. Biochem Pharmacol. 2008 May 15;75(10):1924-34. doi: 10.1016/j.bcp.2008.02.013. Epub 2008 Feb 17.
• [27] Establishment of ion channel and ABC transporter assays in 3D-cultured ReNcell VM on a 384-pillar plate for neurotoxicity potential. Toxicol In Vitro. 2022 Aug;82:105375. doi: 10.1016/j.tiv.2022.105375. Epub 2022 May 10.
• [28] Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J. 2006 Jan-Feb;6(1):27-33. doi: 10.1038/sj.tpj.6500340.