Details of the Drug Combination

General Information of Drug Combination (ID: DCZC0T9)

• Drug Combination Name: Nebivolol + Ramipril
• Indication: Hypertension; Status: Phase 4 [1]
• Component Drugs:
  Nebivolol (DM7F1PA): Small molecular drug
  Ramipril (DM2R68E): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Nebivolol

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]

Nebivolol 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	[7]

Nebivolol Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]

Indication(s) of Ramipril

Disease Entry	ICD 11	Status	REF
Acute heart failure	BD10-BD13	Approved	[3]
Chronic heart failure	BD1Z	Approved	[4]
Congestive heart failure	BD10	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[6]
Stroke	8B20	Investigative	[4]

Ramipril Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[10]
HUMAN angiotensin-converting enzyme (ACE)	TTGFNPD	ACE_HUMAN	Inhibitor	[11]

Ramipril Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[12]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[12]

Ramipril Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[13]
Platelet-derived growth factor subunit B (PDGFB)	OTMFMFC3	PDGFB_HUMAN	Decreases Expression	[14]
Platelet-derived growth factor subunit A (PDGFA)	OTCMZ0W8	PDGFA_HUMAN	Decreases Expression	[14]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[15]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[16]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Hydrolysis	[17]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Increases ADR	[18]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[19]

References

• [1] ClinicalTrials.gov (NCT06104423) Open-label, Multicenter, multinAtionaL, inteRventional Clinical Trial to Assess Efficacy and Safety of the exteMporaneous combInation of Nebivolol and Ramipril in hypertenSIve pAtients
• [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: 7246).
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 202392.
• [4] Ramipril 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: 6339).
• [6] ClinicalTrials.gov (NCT04366050) Ramipril for the Treatment of COVID-19. U.S. National Institutes of Health.
• [7] Nitric oxide mechanisms of nebivolol. Ther Adv Cardiovasc Dis. 2009 Aug;3(4):317-27.
• [8] Nebivolol: a review of its clinical and pharmacological characteristics. Int J Clin Pharmacol Ther. 2006 Aug;44(8):344-57.
• [9] Evaluation of 24 CYP2D6 variants on the metabolism of nebivolol in vitro. Drug Metab Dispos. 2016 Nov;44(11):1828-1831.
• [10] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [11] Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep. 2020 Apr 14;22(5):31.
• [12] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [13] Effects of an angiotensin converting enzyme inhibitor, ramipril, on intracranial circulation in healthy volunteers. off. Br J Clin Pharmacol. 1992 Sep;34(3):224-30. doi: 10.1111/j.1365-2125.1992.tb04128.x.
• [14] Ramipril inhibits in vitro human mesangial cell proliferation and platelet-derived growth factor expression. Exp Nephrol. 1999 May-Jun;7(3):229-35. doi: 10.1159/000020606.
• [15] Distinct vascular and metabolic effects of different classes of anti-hypertensive drugs. Int J Cardiol. 2010 Apr 1;140(1):73-81. doi: 10.1016/j.ijcard.2008.11.017. Epub 2008 Dec 6.
• [16] Additive beneficial cardiovascular and metabolic effects of combination therapy with ramipril and candesartan in hypertensive patients. Eur Heart J. 2007 Jun;28(12):1440-7. doi: 10.1093/eurheartj/ehm101. Epub 2007 May 5.
• [17] Contribution of human esterases to the metabolism of selected drugs of abuse. Toxicol Lett. 2015 Jan 5;232(1):159-66. doi: 10.1016/j.toxlet.2014.10.026. Epub 2014 Oct 24.
• [18] Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial. J Hypertens. 2007 Oct;25(10):2082-92. doi: 10.1097/HJH.0b013e3282b9720e.
• [19] 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.