Details of the Drug Combination

General Information of Drug Combination (ID: DC2X5XQ)

• Drug Combination Name: Candesartan + Hydrochlorothiazide
• Indication: Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Candesartan (DMRK8OT): Small molecular drug
  Hydrochlorothiazide (DMUSZHD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Candesartan

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]

Candesartan 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	[7]

Candesartan Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[10]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[11]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[10]

Candesartan Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[12]
Carbonic anhydrase 1 (CA1)	OTNFBVVQ	CAH1_HUMAN	Decreases Activity	[13]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[14]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[6]
Cytochrome b-245 light chain (CYBA)	OT16N9ZO	CY24A_HUMAN	Decreases Expression	[15]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Increases Expression	[16]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[17]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[18]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[17]
NADPH oxidase 4 (NOX4)	OTTYQ097	NOX4_HUMAN	Decreases Expression	[15]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Affects Response To Substance	[19]

Indication(s) of Hydrochlorothiazide

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Edema	MG29	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Malignant essential hypertension	BA00	Approved	[4]
Prediabetes syndrome	N.A.	Approved	[4]

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	[20]

Hydrochlorothiazide Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[21]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Affects Secretion	[22]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[23]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[23]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[23]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Affects Expression	[23]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[23]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[24]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[24]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[25]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[24]
Prostaglandin E2 receptor EP1 subtype (PTGER1)	OTZV8W66	PE2R1_CANLF	Increases ADR	[24]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Increases ADR	[24]

References

• [1] ClinicalTrials.gov (NCT00383929) Antihypertensive Efficacy and Safety of Candesartan/HCT 32/12.5 and 32/25 mg in Comparison With Candesartan 32 mg
• [2] Candesartan 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: 587).
• [4] Hydrochlorothiazide 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: 4836).
• [6] Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer. Clin Cancer Res. 2006 May 1;12(9):2888-93. doi: 10.1158/1078-0432.CCR-05-2213.
• [7] Candesartan: widening indications for this angiotensin II receptor blocker Expert Opin Pharmacother. 2009 Aug;10(12):1995-2007.
• [8] The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol. 2008 Sep 15;76(6):763-72.
• [9] Product Monograph of Atacand.
• [10] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [11] Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013 Nov;41(11):1888-95.
• [12] A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes. Cardiovasc Drugs Ther. 2008 Dec;22(6):469-78. doi: 10.1007/s10557-008-6131-x. Epub 2008 Aug 5.
• [13] The mechanism of action of angiotensin II is dependent on direct activation of vascular smooth muscle carbonic anhydrase I. Int J Clin Lab Res. 2000;30(3):119-25. doi: 10.1007/s005990070010.
• [14] Candesartan reduces oxidative stress and inflammation in patients with essential hypertension. Hypertens Res. 2003 Sep;26(9):691-7. doi: 10.1291/hypres.26.691.
• [15] Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens. 2008 Jul;26(7):1435-45. doi: 10.1097/HJH.0b013e3283013b6e.
• [16] Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor- activation in human monocytes. J Hypertens. 2012 Jan;30(1):87-96. doi: 10.1097/HJH.0b013e32834dde5f.
• [17] Additive beneficial effects of fenofibrate combined with candesartan in the treatment of hypertriglyceridemic hypertensive patients. Diabetes Care. 2006 Feb;29(2):195-201. doi: 10.2337/diacare.29.02.06.dc05-1418.
• [18] 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.
• [19] Variants of the CYP11B2 gene predict response to therapy with candesartan. Eur J Pharmacol. 2002 Jun 7;445(1-2):151-2. doi: 10.1016/s0014-2999(02)01766-1.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] 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.
• [22] Thiazide-induced hyponatremia. South Med J. 1983 Nov;76(11):1363-7. doi: 10.1097/00007611-198311000-00009.
• [23] 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.
• [24] 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.
• [25] 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.