Details of the Drug Combination

General Information of Drug Combination (ID: DC0BPMF)

Drug Combination Name
Epinephrine Spironolactone
Indication
Disease Entry Status REF
Chronic myelogenous leukemia Investigative [1]
Component Drugs Epinephrine   DM3KJBC Spironolactone   DM2AQ5N
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: KBM-7
Zero Interaction Potency (ZIP) Score: 6.22
Bliss Independence Score: 6.22
Loewe Additivity Score: 7.43
LHighest Single Agent (HSA) Score: 7.43

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
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 [7]
------------------------------------------------------------------------------------
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 [8]
Organic cation transporter 1 (SLC22A1) DTT79CX S22A1_HUMAN Substrate [9]
------------------------------------------------------------------------------------
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 [10]
Sulfotransferase 1A1 (SULT1A1) DEYWLRK ST1A1_HUMAN Metabolism [11]
Thiopurine methyltransferase (TPMT) DEFQ8VO TPMT_HUMAN Metabolism [12]
Catechol O-methyltransferase (COMT) DEV3T4A COMT_HUMAN Metabolism [13]
Monoamine oxidase type A (MAO-A) DERE4TU AOFA_HUMAN Metabolism [14]
------------------------------------------------------------------------------------
Epinephrine Interacts with 33 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Catechol O-methyltransferase (COMT) OTPWKTQG COMT_HUMAN Increases Methylation [15]
Solute carrier family 22 member 3 (SLC22A3) OTQYGVXX S22A3_HUMAN Increases Uptake [16]
Superoxide dismutase (SOD1) OT39TA1L SODC_HUMAN Increases Expression [17]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [17]
Carbonic anhydrase 2 (CA2) OTJRMUAG CAH2_HUMAN Increases Expression [18]
Integrin alpha-V (ITGAV) OTAM7JTR ITAV_HUMAN Increases Expression [18]
Cathepsin K (CTSK) OTT3YX5O CATK_HUMAN Increases Expression [18]
Renin (REN) OT52GZR2 RENI_HUMAN Increases Activity [19]
Insulin (INS) OTZ85PDU INS_HUMAN Decreases Expression [20]
Beta-2 adrenergic receptor (ADRB2) OTSDOX4Q ADRB2_HUMAN Increases Activity [21]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Decreases Cleavage [22]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Increases Expression [22]
Proliferating cell nuclear antigen (PCNA) OTHZ1RIA PCNA_HUMAN Increases Expression [22]
Pyruvate kinase PKM (PKM) OTLHHMC2 KPYM_HUMAN Increases Expression [22]
Alpha-1D adrenergic receptor (ADRA1D) OTW2CD1O ADA1D_HUMAN Increases Activity [23]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Increases Expression [24]
Alpha-1A adrenergic receptor (ADRA1A) OTUIWCL5 ADA1A_HUMAN Increases Activity [23]
Alpha-1B adrenergic receptor (ADRA1B) OTSAYAFD ADA1B_HUMAN Increases Activity [23]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [24]
Tumor necrosis factor ligand superfamily member 6 (FASLG) OTZARCHH TNFL6_HUMAN Increases Expression [24]
Hexokinase-2 (HK2) OTC0GCQO HXK2_HUMAN Increases Expression [22]
Ephrin type-A receptor 4 (EPHA4) OT3AMK0C EPHA4_HUMAN Increases Phosphorylation [25]
Hormone-sensitive lipase (LIPE) OTMMVJ8A LIPS_HUMAN Increases Activity [26]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Increases Expression [22]
P2X purinoceptor 7 (P2RX7) OTNJ9XPL P2RX7_HUMAN Decreases Activity [27]
Leptin (LEP) OT5Q7ODW LEP_HUMAN Increases ADR [28]
Catalase (CAT) OTHEBX9R CATA_HUMAN Decreases Response To Substance [29]
Sulfotransferase 1A3 (SULT1A4) OTHJ8WWV ST1A3_HUMAN Increases Sulfation [30]
Glutathione reductase, mitochondrial (GSR) OTM2TUYM GSHR_HUMAN Increases ADR [28]
Neuron-specific vesicular protein calcyon (CALY) OTQ7EMPU CALY_HUMAN Decreases Secretion [31]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases ADR [28]
Equilibrative nucleoside transporter 4 (SLC29A4) OTWTZXMX S29A4_HUMAN Increases Uptake [16]
Alpha-2A adrenergic receptor (ADRA2A) OTZFGOTP ADA2A_HUMAN Increases ADR [28]
------------------------------------------------------------------------------------
⏷ Show the Full List of 33 DOT(s)
Indication(s) of Spironolactone
Disease Entry ICD 11 Status REF
Chronic heart failure BD1Z Approved [4]
Congestive heart failure BD10 Approved [5]
Edema MG29 Approved [4]
Hyperaldosteronism 5A72 Approved [4]
Coronavirus Disease 2019 (COVID-19) 1D6Y Phase 3 [6]
Spironolactone Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Mineralocorticoid receptor (MR) TT26PHO MCR_HUMAN Modulator [32]
------------------------------------------------------------------------------------
Spironolactone Interacts with 21 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [33]
Cytochrome P450 2C8 (CYP2C8) OTHCWT42 CP2C8_HUMAN Decreases Activity [34]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [35]
Serine/threonine-protein kinase Sgk1 (SGK1) OT301T1U SGK1_HUMAN Increases Expression [36]
Tissue-type plasminogen activator (PLAT) OTQPDNAB TPA_HUMAN Increases Expression [37]
Angiotensinogen (AGT) OTBZLYR3 ANGT_HUMAN Increases Expression [38]
Natriuretic peptides A (NPPA) OTMQNTNX ANF_HUMAN Decreases Expression [39]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Increases Expression [40]
Collagen alpha-1(III) chain (COL3A1) OTT1EMLM CO3A1_HUMAN Decreases Expression [39]
Trefoil factor 1 (TFF1) OTCYQH4F TFF1_HUMAN Increases Expression [41]
Plasminogen activator inhibitor 1 (SERPINE1) OTT0MPQ3 PAI1_HUMAN Decreases Expression [37]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [42]
Mineralocorticoid receptor (NR3C2) OT0F2V2Z MCR_HUMAN Increases Activity [43]
Myb-related protein A (MYBL1) OTBJMC2P MYBA_HUMAN Increases Expression [36]
Androgen receptor (AR) OTUBKAZZ ANDR_HUMAN Affects Binding [44]
Natriuretic peptides B (NPPB) OTSN2IPY ANFB_HUMAN Decreases Expression [39]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [45]
Caspase-7 (CASP7) OTAPJ040 CASP7_HUMAN Increases Activity [45]
Protein GREB1 (GREB1) OTU6ZA26 GREB1_HUMAN Increases Expression [36]
Renin (REN) OT52GZR2 RENI_HUMAN Decreases Response To Substance [46]
Serum paraoxonase/lactonase 3 (PON3) OT80W9TA PON3_HUMAN Increases Hydrolysis [47]
------------------------------------------------------------------------------------
⏷ Show the Full List of 21 DOT(s)

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 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 Spironolactone FDA Label
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: 2875).
6 Spironolactone in Covid-19 Induced ARDS
7 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.
8 Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
9 Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
10 Steroid glucuronides: human circulatory levels and formation by LNCaP cells. J Steroid Biochem Mol Biol. 1991;40(4-6):593-8.
11 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.
12 Adrenal catecholamines and their metabolism in the vitamin A deficient rat. Ann Nutr Metab. 1983;27(3):220-7.
13 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.
14 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.
15 Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.
16 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.
17 Epinephrine upregulates superoxide dismutase in human coronary artery endothelial cells. Free Radic Biol Med. 2001 Jan 15;30(2):148-53.
18 Effects of beta-adrenergic agonists on bone-resorbing activity in human osteoclast-like cells. Biochim Biophys Acta. 2003 May 12;1640(2-3):137-42.
19 Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983 Dec 8;309(23):1414-9. doi: 10.1056/NEJM198312083092303.
20 A receptor mechanism for the inhibition of insulin release by epinephrine in man. J Clin Invest. 1967 Jan;46(1):86-94. doi: 10.1172/JCI105514.
21 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.
22 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.
23 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.
24 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.
25 The platelet P2Y12 receptor contributes to granule secretion through Ephrin A4 receptor. Platelets. 2012;23(8):617-25. doi: 10.3109/09537104.2011.645924. Epub 2012 Jan 24.
26 Hormone-sensitive lipase in human adipose tissue, isolated adipocytes, and cultured adipocytes. Pediatr Res. 1982 Dec;16(12):982-8. doi: 10.1203/00006450-198212000-00002.
27 Epidermal growth factor facilitates epinephrine inhibition of P2X7-receptor-mediated pore formation and apoptosis: a novel signaling network. Endocrinology. 2005 Jan;146(1):164-74. doi: 10.1210/en.2004-1026. Epub 2004 Sep 30.
28 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.
29 Evaluation of cytogenetic and DNA damage in human lymphocytes treated with adrenaline in vitro. Toxicol In Vitro. 2015 Feb;29(1):27-33. doi: 10.1016/j.tiv.2014.08.001. Epub 2014 Aug 27.
30 Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms. Drug Metab Dispos. 2001 Mar;29(3):274-81.
31 Increased arterial pressure in mice with overexpression of the ADHD candidate gene calcyon in forebrain. PLoS One. 2019 Feb 12;14(2):e0211903. doi: 10.1371/journal.pone.0211903. eCollection 2019.
32 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
33 Receptor-dependent regulation of the CYP3A4 gene. Toxicology. 2002 Dec 27;181-182:199-202.
34 Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
35 Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
36 A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor in an MCF-7 Microarray Compendium. Chem Res Toxicol. 2021 Feb 15;34(2):313-329. doi: 10.1021/acs.chemrestox.0c00243. Epub 2021 Jan 6.
37 Effect of spironolactone on impaired fibrinolysis of hypertensive patients. Kidney Blood Press Res. 2002;25(4):260-4. doi: 10.1159/000066348.
38 Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
39 Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001 Apr;37(5):1228-33. doi: 10.1016/s0735-1097(01)01116-0.
40 Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression. Apoptosis. 2006 Apr;11(4):573-9. doi: 10.1007/s10495-006-4919-3.
41 Evaluation of an imaging-based in vitro screening platform for estrogenic activity with OECD reference chemicals. Toxicol In Vitro. 2022 Jun;81:105348. doi: 10.1016/j.tiv.2022.105348. Epub 2022 Mar 18.
42 Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology. 2011 Jul 11;285(1-2):18-24. doi: 10.1016/j.tox.2011.03.015. Epub 2011 Apr 1.
43 The human mineralocorticoid receptor only partially differentiates between different ligands after expression in fission yeast. FEMS Yeast Res. 2005 Apr;5(6-7):627-33. doi: 10.1016/j.femsyr.2004.12.007.
44 Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004 Feb 15;195(2-3):177-86. doi: 10.1016/j.tox.2003.09.012.
45 Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
46 Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study. Hypertension. 1980 Sep-Oct;2(5):672-9. doi: 10.1161/01.hyp.2.5.672.
47 Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.