Details of the Drug Combination

General Information of Drug Combination (ID: DC6X9DN)

• Drug Combination Name: Amlodipine + Eplerenone
• Indication: Metabolic Syndrome; Status: Phase 4 [1]
• Component Drugs:
  Amlodipine (DMBDAZV): Small molecular drug
  Eplerenone (DMF0NQR): 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	[6]

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	[7]

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	[8]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[8]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[9]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[10]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Increases Expression	[11]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Response To Substance	[12]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[13]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[14]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Affects Expression	[15]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[16]
P-selectin (SELP)	OTWR90PK	LYAM3_HUMAN	Decreases Expression	[14]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Activity	[16]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[16]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[16]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[17]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[17]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[18]
Resistin (RETN)	OTW5Z1NH	RETN_HUMAN	Decreases Expression	[17]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases ADR	[19]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[20]

Indication(s) of Eplerenone

Disease Entry	ICD 11	Status	REF
Heart failure	BD10-BD13	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[5]

Eplerenone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN mineralocorticoid receptor (MR)	TT9P1CK	MCR_HUMAN	Antagonist	[5]
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Modulator	[21]

Eplerenone Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[23]

Eplerenone Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Abundance	[23]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Abundance	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Hypertension	DCN0SAO	N. A.	Phase 2	[24]

References

• [1] ClinicalTrials.gov (NCT02034435) Endogenous Renin-Angiotensin-Aldosterone System and Glucose Metabolism
• [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] 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: 2876).
• [5] Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
• [6] 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.
• [7] Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014 Feb;42(2):245-9.
• [8] 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.
• [9] Cell-based high-throughput screening for aromatase inhibitors in the Tox21 10K library. Toxicol Sci. 2015 Oct;147(2):446-57.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [22] Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis. 2003 Sep-Oct;5(5):354-63.
• [23] The relative role of CYP3A4 and CYP3A5 in eplerenone metabolism. Toxicol Lett. 2019 Oct 15;315:9-13.
• [24] ClinicalTrials.gov (NCT01996449) The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension