Details of the Drug Combination

General Information of Drug Combination (ID: DCF4LLD)

• Drug Combination Name: Amlodipine + Ramipril
• Indication: Hypertension; Status: Phase 3 [1]
• Component Drugs:
  Amlodipine (DMBDAZV): Small molecular drug
  Ramipril (DM2R68E): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amlodipine

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]
Stroke	8B20	Investigative	[2]

Amlodipine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated calcium channel alpha-2/delta-1 (CACNA2D1)	TTFK1JQ	CA2D1_HUMAN	Blocker	[8]

Amlodipine 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]

Amlodipine Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[10]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[10]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[11]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[12]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Increases Expression	[13]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Response To Substance	[14]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[15]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[16]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Affects Expression	[17]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[18]
P-selectin (SELP)	OTWR90PK	LYAM3_HUMAN	Decreases Expression	[16]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Activity	[18]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[18]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[18]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[19]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[19]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[20]
Resistin (RETN)	OTW5Z1NH	RETN_HUMAN	Decreases Expression	[19]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases ADR	[21]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[22]

Indication(s) of Ramipril

Disease Entry	ICD 11	Status	REF
Acute heart failure	BD10-BD13	Approved	[4]
Chronic heart failure	BD1Z	Approved	[5]
Congestive heart failure	BD10	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Stroke	8B20	Investigative	[5]

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	[23]
HUMAN angiotensin-converting enzyme (ACE)	TTGFNPD	ACE_HUMAN	Inhibitor	[24]

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	[25]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[25]

Ramipril Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[26]
Platelet-derived growth factor subunit B (PDGFB)	OTMFMFC3	PDGFB_HUMAN	Decreases Expression	[27]
Platelet-derived growth factor subunit A (PDGFA)	OTCMZ0W8	PDGFA_HUMAN	Decreases Expression	[27]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[28]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[29]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Hydrolysis	[30]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Increases ADR	[31]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[32]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Essential Hypertension	DCOOXCJ	N. A.	Phase 4	[33]
Hypertension	DCCHOBT	N. A.	Phase 4	[34]
Hypertension With Metabolic Syndrome	DC4ONE7	N. A.	Phase 1	[35]

References

• [1] ClinicalTrials.gov (NCT00368277) A Safety and Efficacy Trial of Aliskiren 150mg , 300 mg Compared to Ramipril 5mg, 10mg in the Elderly
• [2] Amlodipine FDA Label
• [3] 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: 6981).
• [4] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 202392.
• [5] Ramipril FDA Label
• [6] 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).
• [7] ClinicalTrials.gov (NCT04366050) Ramipril for the Treatment of COVID-19. U.S. National Institutes of Health.
• [8] A first drug combination for the treatment of arterial hypertension with a calcium channel antagonist (amlodipine besylate) and an angiotensin receptor blocker (valsartan): Exforge. Rev Med Liege. 2007 Nov;62(11):688-94.
• [9] Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014 Feb;42(2):245-9.
• [10] Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol. 2000 Feb-Mar;55(11-12):843-52.
• [11] Cell-based high-throughput screening for aromatase inhibitors in the Tox21 10K library. Toxicol Sci. 2015 Oct;147(2):446-57.
• [12] Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by azelnidipine and manidipine. Chem Biol Interact. 2019 Jun 1;306:1-9.
• [13] Amlodipine inhibits cell proliferation via PKD1-related pathway. Biochem Biophys Res Commun. 2008 May 2;369(2):376-81. doi: 10.1016/j.bbrc.2008.02.075. Epub 2008 Feb 25.
• [14] Effects of amlodipine on TGF--induced Smad2, 4 expressions in adriamycin toxicity of rat mesangial cells. Arch Toxicol. 2011 Jun;85(6):663-8. doi: 10.1007/s00204-011-0667-4. Epub 2011 Feb 20.
• [15] Additive beneficial effects of atorvastatin combined with amlodipine in patients with mild-to-moderate hypertension. Int J Cardiol. 2011 Feb 3;146(3):319-25. doi: 10.1016/j.ijcard.2009.07.002. Epub 2009 Aug 3.
• [16] Platelet morphology and plasma indices of platelet activation in essential hypertension: effects of amlodipine-based antihypertensive therapy. Ann Med. 2004;36(7):552-7. doi: 10.1080/07853890410017386.
• [17] Role of transforming growth factor-beta1 in the progression of chronic allograft nephropathy. Nephrol Dial Transplant. 2001;16 Suppl 1:114-6. doi: 10.1093/ndt/16.suppl_1.114.
• [18] G1 cell cycle arrest by amlodipine, a dihydropyridine Ca2+ channel blocker, in human epidermoid carcinoma A431 cells. Biochem Pharmacol. 2007 Apr 1;73(7):943-53. doi: 10.1016/j.bcp.2006.12.011. Epub 2006 Dec 14.
• [19] Amlodipine improves endothelial function and metabolic parameters in patients with hypertension. Int J Cardiol. 2009 Mar 20;133(1):23-31. doi: 10.1016/j.ijcard.2007.11.058. Epub 2008 Jan 15.
• [20] 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.
• [21] Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. JAMA. 2008 Jan 23;299(3):296-307. doi: 10.1001/jama.299.3.296.
• [22] Comparing antihypertensive effect and plasma ciclosporin concentration between amlodipine and valsartan regimens in hypertensive renal transplant patients receiving ciclosporin therapy. Am J Cardiovasc Drugs. 2011 Dec 1;11(6):401-9. doi: 10.2165/11593800-000000000-00000.
• [23] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [24] Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep. 2020 Apr 14;22(5):31.
• [25] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] ClinicalTrials.gov (NCT01180413) Intensive Vasodilator Therapy in Patients With Essential Hypertension
• [34] ClinicalTrials.gov (NCT01922141) Aliskiren Study of Safety and Efficacy in Senior Hypertensives
• [35] ClinicalTrials.gov (NCT00542269) Efficacy and Safety of Aliskiren/Ramipril/Amlodipine Compared With Ramipril/Amlodipine and Aliskiren/Amlodipine in Patients With Metabolic Syndrome