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]

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	[11]
Adrenergic receptor Alpha-1 (ADRA1)	TTG28O6	NOUNIPROTAC	Antagonist	[12]
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	[13]

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	[14]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[17]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[18]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[16]

Carvedilol Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[20]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Increases Activity	[21]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[22]
Potassium channel subfamily K member 3 (KCNK3)	OTWMAV6G	KCNK3_HUMAN	Decreases Activity	[23]
Renin (REN)	OT52GZR2	RENI_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]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[28]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Phosphorylation	[22]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[29]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[22]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Activity	[30]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases ADR	[31]

References

• [1] ClinicalTrials.gov (NCT02294292) Therapeutic Approach to Diastolic Dysfunction in Chronic Liver Disease Patients and Its Impact on Morbidity and Mortality
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• [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).
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• [12] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
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• [22] 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.
• [23] 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.
• [24] Effect of carvedilol and metoprolol on blood pressure, blood flow, and vascular resistance. J Cardiovasc Pharmacol. 1987;10 Suppl 11:S124-9.
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• [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] 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.
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