Details of the Drug Combination

General Information of Drug Combination (ID: DC4JNLS)

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

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Valsartan

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Nephropathy	GC2Z	Investigative	[2]

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	[8]

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	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[10]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[11]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]

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	[13]

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	[14]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[15]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[16]
Serum amyloid P-component (APCS)	OT76JZ8Z	SAMP_HUMAN	Decreases Expression	[17]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Export	[18]
Angiogenin (ANG)	OT3ECS6P	ANGI_HUMAN	Decreases Expression	[7]
Fatty acid-binding protein, adipocyte (FABP4)	OT3DKFOU	FABP4_HUMAN	Decreases Expression	[7]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[19]
Macrophage mannose receptor 1 (MRC1)	OTTVCOPT	MRC1_HUMAN	Decreases Expression	[7]
Cathepsin S (CTSS)	OT3PXIPM	CATS_HUMAN	Decreases Expression	[7]
Hematopoietic progenitor cell antigen CD34 (CD34)	OT1MOFLZ	CD34_HUMAN	Decreases Expression	[7]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Decreases Expression	[7]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[7]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[7]
Coxsackievirus and adenovirus receptor (CXADR)	OT9ZP02A	CXAR_HUMAN	Decreases Expression	[20]
Scavenger receptor cysteine-rich type 1 protein M130 (CD163)	OT2E32LN	C163A_HUMAN	Decreases Expression	[7]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[21]

Indication(s) of Hydrochlorothiazide

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[5]
Edema	MG29	Approved	[5]
Hypertension	BA00-BA04	Approved	[6]
Malignant essential hypertension	BA00	Approved	[5]
Prediabetes syndrome	N.A.	Approved	[5]

Hydrochlorothiazide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Modulator	[22]

Hydrochlorothiazide Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[23]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Affects Secretion	[24]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[25]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[25]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[25]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Affects Expression	[25]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[25]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[26]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[26]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[27]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[26]
Prostaglandin E2 receptor EP1 subtype (PTGER1)	OTZV8W66	PE2R1_CANLF	Increases ADR	[26]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Increases ADR	[26]

References

• [1] ClinicalTrials.gov (NCT00171054) Efficacy and Safety of Valsartan Versus Amlodipine in Postmenopausal Women With Hypertension
• [2] Valsartan 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: 3937).
• [4] Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease
• [5] Hydrochlorothiazide 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: 4836).
• [7] 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.
• [8] Radioligand binding assays: application of [(125)I]angiotensin II receptor binding. Methods Mol Biol. 2009;552:131-41.
• [9] 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.
• [10] 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.
• [11] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] [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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [23] Long-term effect of nifedipine and hydrochlorothiazide on blood pressure and sodium homeostasis at varying levels of salt intake in mildly hypertensive patients. Am J Hypertens. 1991 Sep;4(9):752-60. doi: 10.1093/ajh/4.9.752.
• [24] Thiazide-induced hyponatremia. South Med J. 1983 Nov;76(11):1363-7. doi: 10.1097/00007611-198311000-00009.
• [25] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [26] 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.
• [27] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.