Details of the Drug Combination

General Information of Drug Combination (ID: DCF04R4)

• Drug Combination Name: Epinephrine + Imipramine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Epinephrine (DM3KJBC): Small molecular drug
  Imipramine (DM2NUH3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 6.47
  Bliss Independence Score: 6.47
  Loewe Additivity Score: 7.72
  LHighest Single Agent (HSA) Score: 7.76

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Epinephrine

Disease Entry	ICD 11	Status	REF
Acute asthma	CA23	Approved	[2]
Allergy	4A80-4A85	Approved	[3]
Anaphylaxis	N.A.	Approved	[2]
Bronchiectasis	CA24	Approved	[2]
Bronchitis	CA20	Approved	[2]
Periodontitis	DA0C	Approved	[2]
Pulmonary emphysema	CA21.Z	Approved	[2]
Severe asthma	CA23	Approved	[2]
Asthma	CA23	Investigative	[2]

Epinephrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[6]

Epinephrine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[7]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[8]

Epinephrine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[9]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[10]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[11]
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[12]
Monoamine oxidase type A (MAO-A)	DERE4TU	AOFA_HUMAN	Metabolism	[13]

Epinephrine Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[14]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[15]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[16]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Activity	[17]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Cleavage	[18]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Activity	[19]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[20]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Increases Activity	[19]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Increases Activity	[19]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[20]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases ADR	[21]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[14]
Alpha-2A adrenergic receptor (ADRA2A)	OTZFGOTP	ADA2A_HUMAN	Increases ADR	[21]

Indication(s) of Imipramine

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[4]
Nocturia	MF55	Approved	[5]

Imipramine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Inhibitor	[24]

Imipramine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[25]

Imipramine Interacts with 9 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[26]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[27]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[28]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[29]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[30]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[27]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[27]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[31]
Docosahexaenoic acid omega-hydroxylase (CYP4F11)	DEIZLTN	CP4FB_HUMAN	Metabolism	[32]

Imipramine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[22]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[22]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[22]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[22]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[22]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[22]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[22]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[22]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[22]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[33]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[34]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Expression	[35]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[36]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[37]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Decreases Activity	[38]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[33]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[39]
DnaJ homolog subfamily C member 5 (DNAJC5)	OTCZDXAL	DNJC5_HUMAN	Increases Expression	[40]
SH3 and multiple ankyrin repeat domains protein 2 (SHANK2)	OTSQTPFQ	SHAN2_HUMAN	Decreases Expression	[41]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Epinephrine 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: 509).
• [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: 357).
• [5] Imipramine FDA Label
• [6] Adrenergic activation of electrogenic K+ secretion in guinea pig distal colonic epithelium: involvement of beta1- and beta2-adrenergic receptors. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G269-77.
• [7] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [8] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [9] Steroid glucuronides: human circulatory levels and formation by LNCaP cells. J Steroid Biochem Mol Biol. 1991;40(4-6):593-8.
• [10] Crystal structure of human sulfotransferase SULT1A3 in complex with dopamine and 3'-phosphoadenosine 5'-phosphate. Biochem Biophys Res Commun. 2005 Sep 23;335(2):417-23.
• [11] Adrenal catecholamines and their metabolism in the vitamin A deficient rat. Ann Nutr Metab. 1983;27(3):220-7.
• [12] Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. J Pharmacol Exp Ther. 1994 Mar;268(3):1242-51.
• [13] Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study. J Neurooncol. 2019 Nov;145(2):287-294.
• [14] Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. Epub 2010 Sep 21.
• [15] Epinephrine upregulates superoxide dismutase in human coronary artery endothelial cells. Free Radic Biol Med. 2001 Jan 15;30(2):148-53.
• [16] Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983 Dec 8;309(23):1414-9. doi: 10.1056/NEJM198312083092303.
• [17] Myocardial ischaemia and ventricular arrhthymias precipitated by physiological concentrations of adrenaline in patients with coronary artery disease. Br Heart J. 1992 May;67(5):419-20. doi: 10.1136/hrt.67.5.419-b.
• [18] Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism. Chem Biol Interact. 2023 Jan 5;369:110278. doi: 10.1016/j.cbi.2022.110278. Epub 2022 Nov 22.
• [19] Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human alpha1D- and alpha1B-adrenergic receptors. Cardiovasc Res. 2004 Sep 1;63(4):662-72. doi: 10.1016/j.cardiores.2004.05.014.
• [20] Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells: modulation of Fas/Fas ligand and caspase-3 pathway. Cardiovasc Res. 2000 Feb;45(3):788-94. doi: 10.1016/s0008-6363(99)00369-7.
• [21] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [22] 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.
• [23] N-glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2003 Nov;31(11):1361-8. doi: 10.1124/dmd.31.11.1361.
• [24] Invivo antioxidant status: a putative target of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):220-8.
• [25] Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003 Sep 16;263(1-2):113-22.
• [26] Variability in metabolism of imipramine and desipramine using urinary excretion data. J Anal Toxicol. 2014 Jul-Aug;38(6):368-74.
• [27] Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. J Pharmacol Exp Ther. 1997 Jun;281(3):1199-210.
• [28] Liquid chromatography-tandem mass spectrometry method for measurement of nicotine N-glucuronide: a marker for human UGT2B10 inhibition. J Pharm Biomed Anal. 2011 Jul 15;55(5):964-71.
• [29] QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother. 2005 Mar;39(3):543-6.
• [30] Catalysis of drug oxidation during embryogenesis in human hepatic tissues using imipramine as a model substrate. Drug Metab Dispos. 1999 Nov;27(11):1306-8.
• [31] Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: mechanism of drug interaction between TCAs and phenytoin. Drug Metab Dispos. 2002 Oct;30(10):1102-7.
• [32] Expression and characterization of human cytochrome P450 4F11: putative role in the metabolism of therapeutic drugs and eicosanoids. Toxicol Appl Pharmacol. 2004 Sep 15;199(3):295-304.
• [33] 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.
• [34] Use of peak decay analysis and affinity microcolumns containing silica monoliths for rapid determination of drug-protein dissociation rates. J Chromatogr A. 2011 Apr 15;1218(15):2072-8. doi: 10.1016/j.chroma.2010.09.070. Epub 2010 Oct 16.
• [35] Neutrophil beta(2)-adrenoceptor function in major depression: G(s) coupling, effects of imipramine and relationship to treatment outcome. Eur J Pharmacol. 1999 Dec 15;386(2-3):135-44. doi: 10.1016/s0014-2999(99)00749-9.
• [36] 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.
• [37] Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
• [38] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [39] Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006 Nov;34(11):1868-74. doi: 10.1124/dmd.106.010876. Epub 2006 Aug 23.
• [40] Induction of cysteine string protein after chronic antidepressant treatment in rat frontal cortex. Neurosci Lett. 2001 Apr 6;301(3):183-6. doi: 10.1016/s0304-3940(01)01638-x.
• [41] Establishment of a 13 genes-based molecular prediction score model to discriminate the neurotoxic potential of food relevant-chemicals. Toxicol Lett. 2022 Feb 1;355:1-18. doi: 10.1016/j.toxlet.2021.10.013. Epub 2021 Nov 5.