Details of the Drug Combination

General Information of Drug Combination (ID: DC0UPA1)

• Drug Combination Name: Telmisartan + Hydrochlorothiazide
• Indication: Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Telmisartan (DMS3GX2): Small molecular drug
  Hydrochlorothiazide (DMUSZHD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Telmisartan

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]
Malignant essential hypertension	BA00	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Stroke	8B20	Investigative	[3]

Telmisartan Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[7]
HUMAN type-1 angiotensin II receptor (AGTR1)	TTPKMXQ	AGTR1_HUMAN	Blocker	[8]

Telmisartan Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[10]

Telmisartan Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[12]

Telmisartan Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[13]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[14]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[15]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[16]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[17]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Expression	[18]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Response To Substance	[19]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Increases Expression	[20]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[21]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Activity	[20]
ATP-binding cassette sub-family G member 1 (ABCG1)	OT5BG6MK	ABCG1_HUMAN	Increases Expression	[20]
Stromal cell-derived factor 1 (CXCL12)	OT2QX5LL	SDF1_HUMAN	Decreases Response To Substance	[19]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Decreases Expression	[22]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases Activity	[23]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[17]

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	[24]

Hydrochlorothiazide Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[25]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Affects Secretion	[26]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[27]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[27]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[27]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Affects Expression	[27]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[27]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[28]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[28]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[29]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[28]
Prostaglandin E2 receptor EP1 subtype (PTGER1)	OTZV8W66	PE2R1_CANLF	Increases ADR	[28]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Increases ADR	[28]

References

• [1] ClinicalTrials.gov (NCT01050062) Post-Marketing Surveillance of Micombi Tablets Survey on the Long-term Use
• [2] 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: 592).
• [3] Telmisartan FDA Label
• [4] ClinicalTrials.gov (NCT04359953) Efficacy of Hydroxychloroquine, Telmisartan and Azithromycin on the Survival of Hospitalized Elderly Patients With COVID-19. U.S. National Institutes of Health.
• [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] Deletion of angiotensin II type I receptor reduces hepatic steatosis. J Hepatol. 2009 Jun;50(6):1226-35.
• [8] Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020 Apr 3.
• [9] Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos. 2006 Jul;34(7):1109-15.
• [10] Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos. 2008 Apr;36(4):796-805.
• [11] The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers. Pharmacogenet Genomics. 2011 Sep;21(9):523-30.
• [12] Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin. Drug Metab Dispos. 2012 Apr;40(4):825-35.
• [13] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [14] Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays. Toxicol In Vitro. 2015 Dec 25;30(1 Pt B):241-9.
• [15] 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.
• [16] Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome. Cardiovasc Diabetol. 2005 May 15;4:6. doi: 10.1186/1475-2840-4-6.
• [17] Improvement of endothelial function in patients with hypertension and type 2 diabetes after treatment with telmisartan. Hypertens Res. 2010 Aug;33(8):796-801. doi: 10.1038/hr.2010.107. Epub 2010 Jun 17.
• [18] Effect of telmisartan on ambulatory blood pressure monitoring, plasma brain natriuretic peptide, and oxidative status of serum albumin in hemodialysis patients. Hypertens Res. 2005 Dec;28(12):987-94. doi: 10.1291/hypres.28.987.
• [19] Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma. Hypertension. 2008 Feb;51(2):259-66. doi: 10.1161/HYPERTENSIONAHA.107.099028. Epub 2007 Dec 24.
• [20] 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.
• [21] Comparison of the effects of telmisartan and olmesartan on home blood pressure, glucose, and lipid profiles in patients with hypertension, chronic heart failure, and metabolic syndrome. Hypertens Res. 2008 May;31(5):921-9. doi: 10.1291/hypres.31.921.
• [22] Telmisartan increases the permeability of endothelial cells through zonula occludens-1. Biol Pharm Bull. 2009 Mar;32(3):416-20. doi: 10.1248/bpb.32.416.
• [23] Differential regulation of tefluthrin and telmisartan on the gating charges of I(Na) activation and inactivation as well as on resurgent and persistent I(Na) in a pituitary cell line (GH(3)). Toxicol Lett. 2018 Mar 15;285:104-112. doi: 10.1016/j.toxlet.2018.01.002. Epub 2018 Jan 3.
• [24] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [25] 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.
• [26] Thiazide-induced hyponatremia. South Med J. 1983 Nov;76(11):1363-7. doi: 10.1097/00007611-198311000-00009.
• [27] 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.
• [28] 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.
• [29] 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.