Details of the Drug Combination

General Information of Drug Combination (ID: DCFNVX5)

• Drug Combination Name: Ivabradine + Bisoprolol
• Indication: Heart Failure With Reduced Ejection Fraction; Status: Phase 1 [1]
• Component Drugs:
  Ivabradine (DM0L594): Small molecular drug
  Bisoprolol (DM3UZ95): 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	[6]
Hyperpolarization cyclic nucleotide-gated channel (HCN)	TTKLW9S	NOUNIPROTAC	Inhibitor	[7]

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	[8]

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	[9]

Indication(s) of Bisoprolol

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[4]
Malignant essential hypertension	BA00	Approved	[5]

Bisoprolol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Antagonist	[10]

Bisoprolol Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]

Bisoprolol Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[13]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[14]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[14]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[14]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[14]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[15]

References

• [1] ClinicalTrials.gov (NCT03701880) Early Use of Ivabradine in Heart Failure
• [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] 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: 7129).
• [5] Bisoprolol FDA Label
• [6] 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.
• [7] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [8] Ivabradine: new drug. Best avoided in stable angina. Prescrire Int. 2007 Apr;16(88):53-6.
• [9] 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.
• [10] Antiarrhythmic effect of bisoprolol, a highly selective beta1-blocker, in patients with paroxysmal atrial fibrillation. Int Heart J. 2008 May;49(3):281-93.
• [11] Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63(13):1097-108.
• [12] Drug-drug interactions of beta-adrenoceptor blockers. Arzneimittelforschung. 2003;53(12):814-22.
• [13] 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.
• [14] The effects of 1 month antihypertensive treatment with perindopril, bisoprolol or both on the ex vivo ability of monocytes to secrete inflammatory cytokines. Int J Clin Pharmacol Ther. 2009 Nov;47(11):686-94. doi: 10.5414/cpp47686.
• [15] 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.