Details of the Drug Combination

General Information of Drug Combination (ID: DC9ZUAB)

• Drug Combination Name: Citalopram + Oseltamivir
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Citalopram (DM2G9AE): Small molecular drug
  Oseltamivir (DMGO72P): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 10.86
  Bliss Independence Score: 10.86
  Loewe Additivity Score: 29.4
  LHighest Single Agent (HSA) Score: 29.4

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Citalopram

Disease Entry	ICD 11	Status	REF
Acute coronary syndrome	BA41	Approved	[2]
Anxiety	N.A.	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Insomnia	7A00-7A0Z	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Major depressive disorder	6A70.3	Approved	[2]
Colon cancer	2B90.Z	Investigative	[2]
Gastric cancer	2B72	Investigative	[2]

Citalopram Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Modulator	[7]

Citalopram Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[8]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]

Citalopram Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[13]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]

Citalopram Interacts with 29 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Methylation	[15]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Methylation	[15]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Methylation	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response	[17]
Glutamate receptor 3 (GRIA3)	OT34CNBR	GRIA3_HUMAN	Affects Response To Substance	[18]
Glutamate receptor ionotropic, kainate 2 (GRIK2)	OTQ41U3D	GRIK2_HUMAN	Affects Response To Substance	[18]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[19]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[20]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[20]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Increases Expression	[20]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[20]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[20]
Transgelin (TAGLN)	OTAEZ0KP	TAGL_HUMAN	Decreases Expression	[20]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[20]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Affects Binding	[21]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[22]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[23]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[24]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[25]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[26]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Decreases Expression	[27]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[23]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Expression	[28]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[29]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Response To Substance	[30]
Glutamate receptor 1 (GRIA1)	OT85LOCJ	GRIA1_HUMAN	Affects Response To Substance	[18]
Glutamate receptor ionotropic, kainate 4 (GRIK4)	OTL5EIPA	GRIK4_HUMAN	Increases Response	[31]
Glutamate receptor ionotropic, NMDA 3A (GRIN3A)	OTQS9GYY	NMD3A_HUMAN	Affects Response To Substance	[18]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Increases Response	[32]

Indication(s) of Oseltamivir

Disease Entry	ICD 11	Status	REF
Influenza	1E30-1E32	Approved	[4]
Influenza virus infection	1E30-1E32	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]

Oseltamivir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Influenza Neuraminidase (Influ NA)	TT50QJ3	NRAM_I33A0	Inhibitor	[33]

Oseltamivir Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[34]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[35]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[36]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[37]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[37]

Oseltamivir Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[38]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Metabolism	[39]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Response To Substance	[40]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Citalopram FDA Label
• [3] 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: 7547).
• [4] Oseltamivir FDA Label
• [5] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [6] ClinicalTrials.gov (NCT04261270) A Randomized,Open,Controlled Clinical Study to Evaluate the Efficacy of ASC09F and Ritonavir for 2019-nCoV Pneumonia
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [8] MRP1 polymorphisms associated with citalopram response in patients with major depression. J Clin Psychopharmacol. 2010 Apr;30(2):116-25.
• [9] ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram. Int J Legal Med. 2013 May;127(3):579-86.
• [10] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [11] PharmGKB summary: citalopram pharmacokinetics pathway. Pharmacogenet Genomics. 2011 Nov;21(11):769-72.
• [12] Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1996 Dec;31(6):444-69.
• [13] Antidepressant drugs in the elderly--role of the cytochrome P450 2D6. World J Biol Psychiatry. 2003 Apr;4(2):74-80.
• [14] Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects. Biol Psychiatry. 1999 Sep 15;46(6):839-49.
• [15] Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes. Pharmacogenetics. 1997 Feb;7(1):1-10.
• [16] Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19. Drug Metab Dispos. 2003 Oct;31(10):1255-9. doi: 10.1124/dmd.31.10.1255.
• [17] ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):398-404. doi: 10.1016/j.pnpbp.2007.09.003. Epub 2007 Sep 15.
• [18] Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients. Neuropsychopharmacology. 2009 Jun;34(7):1819-28. doi: 10.1038/npp.2009.4. Epub 2009 Mar 18.
• [19] Antioxidant enzyme and malondialdehyde values in social phobia before and after citalopram treatment. Eur Arch Psychiatry Clin Neurosci. 2004 Aug;254(4):231-5.
• [20] In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol Sci. 2007 Sep;99(1):162-73.
• [21] 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.
• [22] Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay. Toxicol In Vitro. 2015 Oct;29(7):1729-35.
• [23] 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.
• [24] Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans. J Endocrinol Invest. 2010 Oct;33(9):657-62. doi: 10.1007/BF03346666. Epub 2010 Apr 22.
• [25] Cholinergic modulation of the cerebral metabolic response to citalopram in Alzheimer's disease. Brain. 2009 Feb;132(Pt 2):392-401. doi: 10.1093/brain/awn326. Epub 2009 Jan 19.
• [26] The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J Biochem Mol Toxicol. 1999;13(6):338-47. doi: 10.1002/(sici)1099-0461(1999)13:6<338::aid-jbt8>3.0.co;2-7.
• [27] Profiling of enantiopure drugs towards aryl hydrocarbon (AhR), glucocorticoid (GR) and pregnane X (PXR) receptors in human reporter cell lines. Chem Biol Interact. 2014 Feb 5;208:64-76. doi: 10.1016/j.cbi.2013.11.018. Epub 2013 Dec 6.
• [28] Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Gut. 2003 Feb;52(2):300-3. doi: 10.1136/gut.52.2.300.
• [29] Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT). Toxicology. 2019 Jun 15;422:69-75. doi: 10.1016/j.tox.2019.04.012. Epub 2019 Apr 19.
• [30] 5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study. J Clin Psychopharmacol. 2003 Dec;23(6):563-7. doi: 10.1097/01.jcp.0000095350.32154.73.
• [31] Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007 Aug;164(8):1181-8. doi: 10.1176/appi.ajp.2007.06111790.
• [32] Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006 May;78(5):804-814. doi: 10.1086/503820. Epub 2006 Mar 20.
• [33] Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102.
• [34] Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother. 2009 Nov;53(11):4753-61.
• [35] Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21.
• [36] Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos. 2009 Aug;37(8):1676-81.
• [37] FDA Drug Development and Drug Interactions
• [38] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [39] In vitro inhibition of carboxylesterase 1 by Kava (Piper methysticum) Kavalactones. Chem Biol Interact. 2022 Apr 25;357:109883. doi: 10.1016/j.cbi.2022.109883. Epub 2022 Mar 9.
• [40] Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol. 2007 Sep;72(3):686-94. doi: 10.1124/mol.107.036889. Epub 2007 May 30.