Details of the Drug Combination

General Information of Drug Combination (ID: DCRZNJ4)

• Drug Combination Name: Aliskiren + Hydrochlorothiazide
• Indication: Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Aliskiren (DM1BV7W): Small molecular drug
  Hydrochlorothiazide (DMUSZHD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Aliskiren

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]

Aliskiren Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensinogenase renin (REN)	TTB2MXP	RENI_HUMAN	Inhibitor	[5]

Aliskiren Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[7]

Aliskiren 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]

Aliskiren Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[9]

Indication(s) of Hydrochlorothiazide

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[3]
Edema	MG29	Approved	[3]
Hypertension	BA00-BA04	Approved	[4]
Malignant essential hypertension	BA00	Approved	[3]
Prediabetes syndrome	N.A.	Approved	[3]

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	[10]

Hydrochlorothiazide Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[11]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Affects Secretion	[12]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[13]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[13]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[13]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Affects Expression	[13]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[13]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[14]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[14]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[15]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[14]
Prostaglandin E2 receptor EP1 subtype (PTGER1)	OTZV8W66	PE2R1_CANLF	Increases ADR	[14]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Increases ADR	[14]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Cardiovascular Events	DCN1VK5	N. A.	Phase 1	[16]

References

• [1] ClinicalTrials.gov (NCT00787605) Aliskiren HCTZ Compared to Amlodipine in Patients With Stage 2 Systolic Hypertension and Diabetes Mellitus
• [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: 4812).
• [3] Hydrochlorothiazide FDA Label
• [4] 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).
• [5] Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patie... J Renin Angiotensin Aldosterone Syst. 2009 Sep;10(3):157-67.
• [6] Effects of the inhibition of intestinal P-glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys. Biopharm Drug Dispos. 2015 Jan;36(1):15-33.
• [7] Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol. 2011 May;71(5):718-26.
• [8] Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515-31.
• [9] 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.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] 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.
• [12] Thiazide-induced hyponatremia. South Med J. 1983 Nov;76(11):1363-7. doi: 10.1097/00007611-198311000-00009.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] ClinicalTrials.gov (NCT01259297) A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People