Details of the Drug Combination

General Information of Drug Combination (ID: DCUXCY2)

• Drug Combination Name: Carvedilol + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Carvedilol (DMHTEAO): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 16.9
  Bliss Independence Score: 16.9
  Loewe Additivity Score: 9.47
  LHighest Single Agent (HSA) Score: 9.47

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Carvedilol

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Congestive heart failure	BD10	Approved	[3]
Pulmonary hypertension	BB01	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]

Carvedilol Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUAMN alpha-1 adrenergic receptor (ADRA1)	TTDBOI7	ADA1A_HUMAN; ADA1B_HUMAN; ADA1D_HUMAN	Inhibitor	[8]
Adrenergic receptor Alpha-1 (ADRA1)	TTG28O6	NOUNIPROTAC	Antagonist	[9]
HUMAN beta adrenergic receptor (BAR)	TTJB8UY	ADRB1_HUMAN; ADRB2_HUMAN; ADRB3_HUMAN	Antagonist	[4]

Carvedilol 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]

Carvedilol Interacts with 7 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]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[13]

Carvedilol Interacts with 28 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Affects Glucuronidation	[17]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[18]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Increases Activity	[19]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[20]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Phosphorylation	[21]
Potassium channel subfamily K member 3 (KCNK3)	OTWMAV6G	KCNK3_HUMAN	Decreases Activity	[22]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Expression	[23]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[24]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[25]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[26]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Decreases Expression	[27]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[28]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[29]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[30]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[31]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Phosphorylation	[20]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[25]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Affects Activity	[32]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[33]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Increases Expression	[34]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[35]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[20]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[36]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[33]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[30]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Activity	[37]
Vascular endothelial growth factor receptor 2 (KDR)	OT15797V	VGFR2_HUMAN	Increases ADR	[38]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases ADR	[38]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[5]
Acute myeloid leukaemia	2A60	Approved	[6]
Adult acute monocytic leukemia	N.A.	Approved	[5]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[5]
Leukemia	N.A.	Approved	[5]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[40]

Idarubicin 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	[41]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[42]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[42]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[43]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[43]

Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[39]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[44]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[39]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[45]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[39]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[46]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[39]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[47]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[39]

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] Carvedilol 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: 551).
• [4] Can beta-adrenergic blockers be used in the treatment of COVID-19 Med Hypotheses. 2020 May 5;142:109809.
• [5] Idarubicin FDA Label
• [6] 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: 7083).
• [7] Involvement of human hepatic UGT1A1, UGT2B4, and UGT2B7 in the glucuronidation of carvedilol. Drug Metab Dispos. 2004 Feb;32(2):235-9. doi: 10.1124/dmd.32.2.235.
• [8] Carvedilol increases the production of interleukin-12 and interferon-gamma and improves the survival of mice infected with the encephalomyocarditis virus. J Am Coll Cardiol. 2003 Jan 15;41(2):340-5.
• [9] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
• [10] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [11] Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro. Drug Des Devel Ther. 2016 Jun 8;10:1909-16.
• [12] Pharmacokinetic interactions study between carvedilol and some antidepressants in rat liver microsomes - a comparative study. Med Pharm Rep. 2019 Apr;92(2):158-164.
• [13] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [14] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [15] In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol. Drug Metab Dispos. 1997 Aug;25(8):970-7.
• [16] The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro. Eur J Drug Metab Pharmacokinet. 2016 Feb;41(1):79-86.
• [17] Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol. J Pharm Pharm Sci. 2006;9(1):101-12.
• [18] Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol. 2006 Jun;20(3):273-82. doi: 10.1111/j.1472-8206.2006.00408.x.
• [19] Agonist actions of "beta-blockers" provide evidence for two agonist activation sites or conformations of the human beta1-adrenoceptor. Mol Pharmacol. 2003 Jun;63(6):1312-21. doi: 10.1124/mol.63.6.1312.
• [20] A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. doi: 10.1073/pnas.0707936104. Epub 2007 Oct 9.
• [21] Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555-60.
• [22] Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels. Br J Pharmacol. 2011 Jul;163(5):1099-110. doi: 10.1111/j.1476-5381.2011.01319.x.
• [23] Effect of carvedilol and metoprolol on blood pressure, blood flow, and vascular resistance. J Cardiovasc Pharmacol. 1987;10 Suppl 11:S124-9.
• [24] Renal and cardiac function during alpha1-beta-blockade in congestive heart failure. Scand J Clin Lab Invest. 2002;62(2):97-104. doi: 10.1080/003655102753611717.
• [25] [Arterial hypertension and oxidative stress induced by cyclosporin. Effect of carvedilol]. Ann Ital Med Int. 2001 Apr-Jun;16(2):101-5.
• [26] Effects of carvedilol on atrial natriuretic peptide, catecholamines, and hemodynamics in hypertension at rest and during exercise. J Cardiovasc Pharmacol. 1992;19 Suppl 1:S90-6. doi: 10.1097/00005344-199219001-00018.
• [27] Lower plasma noradrenaline and blood viscosity on carvedilol vs atenolol in men with recent myocardial infarction. Blood Press. 2002;11(6):377-84. doi: 10.1080/080370502321095357.
• [28] After myocardial infarction carvedilol improves insulin resistance compared to metoprolol. Clin Res Cardiol. 2006 Feb;95(2):99-104. doi: 10.1007/s00392-006-0336-4. Epub 2006 Feb 6.
• [29] Effects of carvedilol on oxidative stress in polymorphonuclear and mononuclear cells in patients with essential hypertension. Am J Med. 2004 Apr 1;116(7):460-5. doi: 10.1016/j.amjmed.2003.10.029.
• [30] 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.
• [31] Carvedilol inhibits endothelin-1 biosynthesis in cultured human coronary artery endothelial cells. J Mol Cell Cardiol. 1998 Jan;30(1):167-73. doi: 10.1006/jmcc.1997.0582.
• [32] Adrenoceptor blockade alters plasma gelatinase activity in patients with heart failure and MMP-9 promoter activity in a human cell line (ECV304). Pharmacol Res. 2006 Jul;54(1):57-64. doi: 10.1016/j.phrs.2006.02.006. Epub 2006 Feb 28.
• [33] Effect of carvedilol on plasma adiponectin concentration in patients with chronic heart failure. Circ J. 2009 Jun;73(6):1067-73. doi: 10.1253/circj.cj-08-1026. Epub 2009 Apr 14.
• [34] Reduced expression of endothelial connexins 43 and 37 in hypertensive rats is rectified after 7-day carvedilol treatment. Am J Hypertens. 2006 Feb;19(2):129-35. doi: 10.1016/j.amjhyper.2005.08.020.
• [35] Carvedilol modulates in-vitro granulocyte-macrophage colony-stimulating factor-induced interleukin-10 production in U937 cells and human monocytes. Immunol Invest. 2003 Feb;32(1-2):43-58. doi: 10.1081/imm-120019207.
• [36] Antiarrhythmic drug carvedilol inhibits HERG potassium channels. Cardiovasc Res. 2001 Feb 1;49(2):361-70. doi: 10.1016/s0008-6363(00)00265-0.
• [37] Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation. 2003 May 20;107(19):2459-66. doi: 10.1161/01.CIR.0000068316.53218.49. Epub 2003 May 12.
• [38] 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.
• [39] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [40] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [41] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [42] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [43] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [44] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
• [45] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [46] The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
• [47] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.