Details of the Drug Combination

General Information of Drug Combination (ID: DC55AFZ)

• Drug Combination Name: Amlodipine + Valsartan
• Indication: Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Amlodipine (DMBDAZV): Small molecular drug
  Valsartan (DMREUQ6): 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	[7]

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	[8]

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	[9]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[9]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[10]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[11]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Increases Expression	[12]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Response To Substance	[13]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[14]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[15]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Affects Expression	[16]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[17]
P-selectin (SELP)	OTWR90PK	LYAM3_HUMAN	Decreases Expression	[15]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Activity	[17]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[17]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[18]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[18]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[19]
Resistin (RETN)	OTW5Z1NH	RETN_HUMAN	Decreases Expression	[18]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases ADR	[20]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[21]

Indication(s) of Valsartan

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Nephropathy	GC2Z	Investigative	[4]

Valsartan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[23]

Valsartan Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[24]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[25]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[26]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[27]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[24]

Valsartan Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[28]

Valsartan Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Expression	[29]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[30]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[31]
Serum amyloid P-component (APCS)	OT76JZ8Z	SAMP_HUMAN	Decreases Expression	[32]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Export	[33]
Angiogenin (ANG)	OT3ECS6P	ANGI_HUMAN	Decreases Expression	[22]
Fatty acid-binding protein, adipocyte (FABP4)	OT3DKFOU	FABP4_HUMAN	Decreases Expression	[22]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[34]
Macrophage mannose receptor 1 (MRC1)	OTTVCOPT	MRC1_HUMAN	Decreases Expression	[22]
Cathepsin S (CTSS)	OT3PXIPM	CATS_HUMAN	Decreases Expression	[22]
Hematopoietic progenitor cell antigen CD34 (CD34)	OT1MOFLZ	CD34_HUMAN	Decreases Expression	[22]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Decreases Expression	[22]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[22]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[22]
Coxsackievirus and adenovirus receptor (CXADR)	OT9ZP02A	CXAR_HUMAN	Decreases Expression	[35]
Scavenger receptor cysteine-rich type 1 protein M130 (CD163)	OT2E32LN	C163A_HUMAN	Decreases Expression	[22]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[21]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Hypertension	DCGCOKA	N. A.	Phase 3	[36]
Hypertension; Hypertrophy, Left Ventricular	DCYIBJG	N. A.	Phase 1	[37]

References

• [1] ClinicalTrials.gov (NCT00523549) The Effects of Systolic Blood Pressure Lowering on Diastolic Function Using Valsartan + Amlodipine in Patients With Hypertension and Diastolic Dysfunction
• [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] Valsartan 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: 3937).
• [6] Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease
• [7] 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.
• [8] Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014 Feb;42(2):245-9.
• [9] 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.
• [10] Cell-based high-throughput screening for aromatase inhibitors in the Tox21 10K library. Toxicol Sci. 2015 Oct;147(2):446-57.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Valsartan improves adipose tissue function in humans with impaired glucose metabolism: a randomized placebo-controlled double-blind trial. PLoS One. 2012;7(6):e39930. doi: 10.1371/journal.pone.0039930. Epub 2012 Jun 29.
• [23] Radioligand binding assays: application of [(125)I]angiotensin II receptor binding. Methods Mol Biol. 2009;552:131-41.
• [24] Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006 Jul;34(7):1247-54.
• [25] Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions. Int J Mol Sci. 2018 Mar 14;19(3). pii: E855.
• [26] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [27] Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos. 2011 Jun;39(6):1031-8.
• [28] In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonists. Eur J Clin Pharmacol. 2000 May;56(2):135-40.
• [29] Uric acid accumulation in the kidney triggers mast cell degranulation and aggravates renal oxidative stress. Toxicology. 2023 Jan 1;483:153387. doi: 10.1016/j.tox.2022.153387. Epub 2022 Dec 1.
• [30] Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists. Hypertension. 1999 Mar;33(3):850-5. doi: 10.1161/01.hyp.33.3.850.
• [31] [The relationship between the gene polymorphism of TGF-beta1 and early renal injury in patients with essential hypertension, and the effect of the gene polymorphism of TGF- beta1 on the individual treatment with valsartan]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Aug;24(4):428-31.
• [32] C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005 Sep 6;112(10):1428-34. doi: 10.1161/CIRCULATIONAHA.104.508465. Epub 2005 Aug 29.
• [33] Is renoprotection by angiotensin receptor blocker dependent on blood pressure?: the Saitama Medical School, Albuminuria Reduction in Diabetics with Valsartan (STAR) study. Hypertens Res. 2007 Jun;30(6):529-33. doi: 10.1291/hypres.30.529.
• [34] Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2002 Nov 5;106(19):2454-8. doi: 10.1161/01.cir.0000036747.68104.ac.
• [35] Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells. J Gen Virol. 2010 Aug;91(Pt 8):1959-1970. doi: 10.1099/vir.0.020065-0. Epub 2010 Apr 14.
• [36] ClinicalTrials.gov (NCT01365481) Safety and Tolerability of Valsartan in Children 6 to 17 Years of Age
• [37] ClinicalTrials.gov (NCT00446563) Efficacy and Safety of Valsartan in Combination With Amlodipine Compared to Losartan Plus Hydrochlorothiazide in Patients With Hypertension and Left Ventricular Hypertrophy