Details of the Drug Combination

General Information of Drug Combination (ID: DCEZK68)

• Drug Combination Name: Bendroflumethiazide + Amiloride
• Indication: Heart Failure; Status: Phase 1 [1]
• Component Drugs:
  Bendroflumethiazide (DM7EVLC): Small molecular drug
  Amiloride (DMRTSGP): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bendroflumethiazide

Disease Entry	ICD 11	Status	REF
High blood pressure	BA00	Approved	[2]

Bendroflumethiazide Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Solute carrier family 12 member 3 (SLC12A3)	TTP362L	S12A3_HUMAN	Blocker	[5]
Solute carrier family 12 member 1 (SLC12A1)	TTS087L	S12A1_HUMAN	Blocker	[5]

Bendroflumethiazide Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Thiopurine S-methyltransferase (TPMT)	OTFOX70W	TPMT_HUMAN	Decreases Activity	[6]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[7]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Affects Expression	[8]

Indication(s) of Amiloride

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[3]
Edema	MG29	Approved	[4]

Amiloride Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acid-sensing ion channel 1 (ASIC1)	TTRJYB6	ASIC1_HUMAN	Modulator	[10]

Amiloride Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[11]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[12]

Amiloride Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Diamine oxidase (AOC1)	OTRC220K	AOC1_HUMAN	Decreases Activity	[13]
3-phosphoinositide-dependent protein kinase 1 (PDPK1)	OTT09ZVP	PDPK1_HUMAN	Decreases Phosphorylation	[14]
Dysferlin (DYSF)	OTNSKJU0	DYSF_HUMAN	Decreases Expression	[15]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Activity	[16]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[17]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[18]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Phosphorylation	[14]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[19]
Myogenic factor 5 (MYF5)	OTTVO2S5	MYF5_HUMAN	Increases Expression	[15]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[20]
Pancreas/duodenum homeobox protein 1 (PDX1)	OTX1DKRA	PDX1_HUMAN	Decreases Uptake	[21]
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA)	OT7Y43A1	PP1A_HUMAN	Decreases Phosphorylation	[14]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[19]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[22]
Glutamate receptor-interacting protein 1 (GRIP1)	OT958HK1	GRIP1_HUMAN	Affects Response To Substance	[23]

References

• [1] ClinicalTrials.gov (NCT05753059) Mechanisms of Diuretic Resistance in Heart Failure, Aim 2
• [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: 7122).
• [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: 2421).
• [4] Amiloride FDA Label
• [5] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [6] Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol. 1996;49(5):393-6.
• [7] Low renin hypertension. A distinct entity. Lancet. 1976 Oct 30;2(7992):930-2. doi: 10.1016/s0140-6736(76)90892-8.
• [8] Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990 Apr 14;300(6730):975-8. doi: 10.1136/bmj.300.6730.975.
• [9] Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leuk Res. 2007 Apr;31(4):507-14. doi: 10.1016/j.leukres.2006.06.015. Epub 2006 Aug 1.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol. 2006 Jun;290(6):C1521-31.
• [12] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [13] Diamine oxidase is the amiloride-binding protein and is inhibited by amiloride analogues. J Biol Chem. 1994 Apr 1;269(13):9921-5.
• [14] Role of HER-2/neu signaling in sensitivity to tumor necrosis factor-related apoptosis-inducing ligand: enhancement of TRAIL-mediated apoptosis by amiloride. J Cell Biochem. 2005 Oct 1;96(2):376-89. doi: 10.1002/jcb.20512.
• [15] In vivo and in vitro dysferlin expression in human muscle satellite cells. J Neuropathol Exp Neurol. 2004 Oct;63(10):1104-13. doi: 10.1093/jnen/63.10.1104.
• [16] Amplification of urokinase gene in prostate cancer. Cancer Res. 2001 Jul 15;61(14):5340-4.
• [17] Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
• [18] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [19] 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.
• [20] Reduction in the radiation-induced late S phase and G2 blocks in HL-60 cell populations by amiloride, an efficient inhibitor of the Na+/H+ transporter. Cancer Res. 1998 Feb 1;58(3):413-20.
• [21] PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant. 2005;14(9):637-45. doi: 10.3727/000000005783982648.
• [22] Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006 Nov;34(11):1868-74. doi: 10.1124/dmd.106.010876. Epub 2006 Aug 23.
• [23] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.