Details of the Drug Combination

General Information of Drug Combination (ID: DCE62MP)

• Drug Combination Name: Aliskiren + Ramipril
• Indication: Heart Failure; Status: Phase 1 [1]
• Component Drugs:
  Aliskiren (DM1BV7W): Small molecular drug
  Ramipril (DM2R68E): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Aliskiren

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

Aliskiren Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensinogenase renin (REN)	TTB2MXP	RENI_HUMAN	Inhibitor	[7]

Aliskiren Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[9]

Aliskiren Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Aliskiren Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[11]

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	[12]
HUMAN angiotensin-converting enzyme (ACE)	TTGFNPD	ACE_HUMAN	Inhibitor	[13]

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	[14]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[14]

Ramipril Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[15]
Platelet-derived growth factor subunit B (PDGFB)	OTMFMFC3	PDGFB_HUMAN	Decreases Expression	[16]
Platelet-derived growth factor subunit A (PDGFA)	OTCMZ0W8	PDGFA_HUMAN	Decreases Expression	[16]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[17]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[18]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Hydrolysis	[19]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Increases ADR	[20]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[21]

References

• [1] ClinicalTrials.gov (NCT00923156) Effects of Aliskiren, Ramipril, and the Combination on Levels of Angiotensin II in Patients With Decompensated Systolic 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: 4812).
• [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] Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patie... J Renin Angiotensin Aldosterone Syst. 2009 Sep;10(3):157-67.
• [8] Effects of the inhibition of intestinal P-glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys. Biopharm Drug Dispos. 2015 Jan;36(1):15-33.
• [9] Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol. 2011 May;71(5):718-26.
• [10] Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515-31.
• [11] 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.
• [12] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [13] Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep. 2020 Apr 14;22(5):31.
• [14] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.