Details of the Drug Combination

General Information of Drug Combination (ID: DCU667O)

• Drug Combination Name: Ivabradine + Carvedilol
• Indication: Diastolic Dysfunction; Status: Phase 1 [1]
• Component Drugs:
  Ivabradine (DM0L594): Small molecular drug
  Carvedilol (DMHTEAO): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ivabradine

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Chronic heart failure	BD1Z	Approved	[3]

Ivabradine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sinus node I(f) channel (SA node IfC)	TTFCQYU	NOUNIPROTAC	Modulator	[7]
Hyperpolarization cyclic nucleotide-gated channel (HCN)	TTKLW9S	NOUNIPROTAC	Inhibitor	[8]

Ivabradine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]

Ivabradine Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[10]

Indication(s) of Carvedilol

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Congestive heart failure	BD10	Approved	[5]
Pulmonary hypertension	BB01	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[6]

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	[12]
Adrenergic receptor Alpha-1 (ADRA1)	TTG28O6	NOUNIPROTAC	Antagonist	[13]
HUMAN beta adrenergic receptor (BAR)	TTJB8UY	ADRB1_HUMAN; ADRB2_HUMAN; ADRB3_HUMAN	Antagonist	[6]

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	[14]

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	[15]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[18]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[20]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[17]

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	[21]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[22]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Increases Activity	[23]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[24]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Phosphorylation	[25]
Potassium channel subfamily K member 3 (KCNK3)	OTWMAV6G	KCNK3_HUMAN	Decreases Activity	[26]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Expression	[27]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[28]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[29]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[30]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Decreases Expression	[31]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[32]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[33]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[34]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[35]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Phosphorylation	[24]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[29]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Affects Activity	[36]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[37]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Increases Expression	[38]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[39]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[24]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[40]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[37]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[34]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Activity	[41]
Vascular endothelial growth factor receptor 2 (KDR)	OT15797V	VGFR2_HUMAN	Increases ADR	[42]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases ADR	[42]

References

• [1] ClinicalTrials.gov (NCT02294292) Therapeutic Approach to Diastolic Dysfunction in Chronic Liver Disease Patients and Its Impact on Morbidity and Mortality
• [2] 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: 2357).
• [3] Ivabradine FDA Label
• [4] Carvedilol 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: 551).
• [6] Can beta-adrenergic blockers be used in the treatment of COVID-19 Med Hypotheses. 2020 May 5;142:109809.
• [7] Ivabradine - the first selective sinus node If channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006 February; 60(2): 222-228.
• [8] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [9] Ivabradine: new drug. Best avoided in stable angina. Prescrire Int. 2007 Apr;16(88):53-6.
• [10] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [11] 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.
• [12] 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.
• [13] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
• [14] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [15] Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro. Drug Des Devel Ther. 2016 Jun 8;10:1909-16.
• [16] Pharmacokinetic interactions study between carvedilol and some antidepressants in rat liver microsomes - a comparative study. Med Pharm Rep. 2019 Apr;92(2):158-164.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro. Eur J Drug Metab Pharmacokinet. 2016 Feb;41(1):79-86.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Effect of carvedilol and metoprolol on blood pressure, blood flow, and vascular resistance. J Cardiovasc Pharmacol. 1987;10 Suppl 11:S124-9.
• [28] 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.
• [29] [Arterial hypertension and oxidative stress induced by cyclosporin. Effect of carvedilol]. Ann Ital Med Int. 2001 Apr-Jun;16(2):101-5.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] Antiarrhythmic drug carvedilol inhibits HERG potassium channels. Cardiovasc Res. 2001 Feb 1;49(2):361-70. doi: 10.1016/s0008-6363(00)00265-0.
• [41] 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.
• [42] 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.