Details of the Drug Combination

General Information of Drug Combination (ID: DC4QOFN)

• Drug Combination Name: Lisinopril + Telmisartan
• Indication: Kidney, Polycystic; Status: Phase 3 [1]
• Component Drugs:
  Lisinopril (DMUOK4C): Small molecular drug
  Telmisartan (DMS3GX2): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lisinopril

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Myocardial infarction	BA41-BA43	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]
High blood pressure	BA00	Investigative	[2]

Lisinopril Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[8]
HUMAN angiotensin-converting enzyme (ACE)	TTGFNPD	ACE_HUMAN	Inhibitor	[4]

Lisinopril Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[9]

Lisinopril Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Decreases Activity	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[11]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[12]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[12]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Secretion	[13]
Insulin-like growth factor-binding protein 1 (IGFBP1)	OT6UQV2K	IBP1_HUMAN	Increases Expression	[14]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[15]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[16]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[17]

Indication(s) of Telmisartan

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[5]
Malignant essential hypertension	BA00	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Stroke	8B20	Investigative	[6]

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	[18]
HUMAN type-1 angiotensin II receptor (AGTR1)	TTPKMXQ	AGTR1_HUMAN	Blocker	[19]

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	[20]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[20]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[21]

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	[22]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[23]

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	[24]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[25]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[26]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[27]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[28]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Expression	[29]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Response To Substance	[30]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Increases Expression	[31]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[32]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Activity	[31]
ATP-binding cassette sub-family G member 1 (ABCG1)	OT5BG6MK	ABCG1_HUMAN	Increases Expression	[31]
Stromal cell-derived factor 1 (CXCL12)	OT2QX5LL	SDF1_HUMAN	Decreases Response To Substance	[30]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Decreases Expression	[33]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases Activity	[34]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[28]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Kidney, Polycystic	DCOC4OX	N. A.	Phase 1	[35]

References

• [1] ClinicalTrials.gov (NCT01885559) HALT Progression of Polycystic Kidney Disease Study B
• [2] Lisinopril FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc. 2020 Apr 7;9(7):e016219.
• [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: 592).
• [6] Telmisartan FDA Label
• [7] 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.
• [8] Involvement of vascular angiotensin II-forming enzymes in the progression of aortic abdominal aneurysms in angiotensin II- infused ApoE-deficient m... J Atheroscler Thromb. 2009 Jun;16(3):164-71.
• [9] Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharm Res. 2007 Apr;30(4):507-18.
• [10] Targeted catalytic inactivation of angiotensin converting enzyme by lisinopril-coupled transition-metal chelates. J Am Chem Soc. 2012 Feb 22;134(7):3396-410. doi: 10.1021/ja208791f. Epub 2012 Feb 10.
• [11] Hemodynamic responses to converting enzyme inhibition in patients with renal disease. Am J Hypertens. 1989 Aug;2(8):599-603. doi: 10.1093/ajh/2.8.599.
• [12] Effects of lisinopril on cardiorespiratory, neuroendocrine, and renal function in patients with asymptomatic left ventricular dysfunction. Br Heart J. 1993 Jun;69(6):512-5. doi: 10.1136/hrt.69.6.512.
• [13] Different effects of angiotensin converting enzyme inhibitors on endothelin-1 and nitric oxide balance in human vascular endothelial cells: evidence of an oxidant-sensitive pathway. Mediators Inflamm. 2008;2008:305087. doi: 10.1155/2008/305087. Epub 2008 Dec 1.
• [14] Tissue availability of insulin-like growth factor I is inversely related to insulin resistance in essential hypertension: effects of angiotensin converting enzyme inhibition. J Hypertens. 1998 Jun;16(6):863-70. doi: 10.1097/00004872-199816060-00018.
• [15] Reduced bcl-2 concentrations in hypertensive patients after lisinopril or nifedipine administration. Am J Hypertens. 1999 Jan;12(1 Pt 1):73-5. doi: 10.1016/s0895-7061(98)00217-9.
• [16] 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.
• [17] 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.
• [18] Deletion of angiotensin II type I receptor reduces hepatic steatosis. J Hepatol. 2009 Jun;50(6):1226-35.
• [19] Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020 Apr 3.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] ClinicalTrials.gov (NCT00283686) HALT Progression of Polycystic Kidney Disease Study A