Details of the Drug Combination

General Information of Drug Combination (ID: DCLALVW)

• Drug Combination Name: Epinephrine + Dronedarone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Epinephrine (DM3KJBC): Small molecular drug
  Dronedarone (DMA8FS5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.96
  Bliss Independence Score: 3.96
  Loewe Additivity Score: 5.14
  LHighest Single Agent (HSA) Score: 5.15

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	[5]

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	[6]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[7]

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	[8]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[9]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[10]
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[11]
Monoamine oxidase type A (MAO-A)	DERE4TU	AOFA_HUMAN	Metabolism	[12]

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	[13]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[14]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Increases Expression	[15]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[15]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Increases Expression	[16]
Integrin alpha-V (ITGAV)	OTAM7JTR	ITAV_HUMAN	Increases Expression	[16]
Cathepsin K (CTSK)	OTT3YX5O	CATK_HUMAN	Increases Expression	[16]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[17]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[18]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Activity	[19]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Cleavage	[20]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Increases Expression	[20]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Increases Expression	[20]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Increases Expression	[20]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Activity	[21]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[22]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Increases Activity	[21]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Increases Activity	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[22]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[22]
Hexokinase-2 (HK2)	OTC0GCQO	HXK2_HUMAN	Increases Expression	[20]
Ephrin type-A receptor 4 (EPHA4)	OT3AMK0C	EPHA4_HUMAN	Increases Phosphorylation	[23]
Hormone-sensitive lipase (LIPE)	OTMMVJ8A	LIPS_HUMAN	Increases Activity	[24]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[20]
P2X purinoceptor 7 (P2RX7)	OTNJ9XPL	P2RX7_HUMAN	Decreases Activity	[25]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Increases ADR	[26]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Response To Substance	[27]
Sulfotransferase 1A3 (SULT1A4)	OTHJ8WWV	ST1A3_HUMAN	Increases Sulfation	[28]
Glutathione reductase, mitochondrial (GSR)	OTM2TUYM	GSHR_HUMAN	Increases ADR	[26]
Neuron-specific vesicular protein calcyon (CALY)	OTQ7EMPU	CALY_HUMAN	Decreases Secretion	[29]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases ADR	[26]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[14]
Alpha-2A adrenergic receptor (ADRA2A)	OTZFGOTP	ADA2A_HUMAN	Increases ADR	[26]

Indication(s) of Dronedarone

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[4]
Atrial fibrillation	BC81.3	Withdrawn from market	[4]

Dronedarone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated potassium channel Kv1.5 (KCNA5)	TTW0CMT	KCNA5_HUMAN	Blocker	[30]
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Inhibitor	[31]

Dronedarone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[32]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[33]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[34]

Dronedarone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Response To Substance	[35]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Response To Substance	[35]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Response To Substance	[35]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[36]
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Decreases Expression	[35]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[35]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[35]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[35]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[35]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[35]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[36]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[36]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[35]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[37]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[38]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Metabolism	[35]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[35]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Metabolism	[35]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Metabolism	[35]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Metabolism	[35]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Increases Metabolism	[35]

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] 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: 7465).
• [5] 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.
• [6] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [7] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [8] Steroid glucuronides: human circulatory levels and formation by LNCaP cells. J Steroid Biochem Mol Biol. 1991;40(4-6):593-8.
• [9] 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.
• [10] Adrenal catecholamines and their metabolism in the vitamin A deficient rat. Ann Nutr Metab. 1983;27(3):220-7.
• [11] 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.
• [12] 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.
• [13] 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.
• [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] 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.
• [17] Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983 Dec 8;309(23):1414-9. doi: 10.1056/NEJM198312083092303.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms. Drug Metab Dispos. 2001 Mar;29(3):274-81.
• [29] 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.
• [30] New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.
• [31] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [32] Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf. 2012 Nov;11(6):1023-45.
• [33] Effect of dronedarone on the pharmacokinetics of carvedilol following oral administration to rats. Eur J Pharm Sci. 2018 Jan 1;111:13-19.
• [34] Inactivation of human cytochrome P450 3A4 and 3A5 by dronedarone and N-desbutyl dronedarone. Mol Pharmacol. 2016 Jan;89(1):1-13.
• [35] The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. Arch Toxicol. 2018 Jun;92(6):1969-1981. doi: 10.1007/s00204-018-2196-x. Epub 2018 Apr 3.
• [36] Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone. Toxicol Sci. 2013 Feb;131(2):480-90. doi: 10.1093/toxsci/kfs298. Epub 2012 Nov 7.
• [37] Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet. 2002;17(4):374-7. doi: 10.2133/dmpk.17.374.
• [38] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.