Details of the Drug Combination

General Information of Drug Combination (ID: DC6OONO)

• Drug Combination Name: Spironolactone + Dihydralazine
• Indication: Aortic Stenosis, Severe; Status: Phase 3 [1]
• Component Drugs:
  Spironolactone (DM2AQ5N): Small molecular drug
  Dihydralazine (DMZIXU9): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Spironolactone

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Congestive heart failure	BD10	Approved	[3]
Edema	MG29	Approved	[2]
Hyperaldosteronism	5A72	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]

Spironolactone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Modulator	[6]

Spironolactone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[7]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[8]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[9]
Serine/threonine-protein kinase Sgk1 (SGK1)	OT301T1U	SGK1_HUMAN	Increases Expression	[10]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[11]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[12]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[13]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[14]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[13]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[15]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Decreases Expression	[11]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[16]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[17]
Myb-related protein A (MYBL1)	OTBJMC2P	MYBA_HUMAN	Increases Expression	[10]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Binding	[18]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[19]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[19]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Increases Expression	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Response To Substance	[20]
Serum paraoxonase/lactonase 3 (PON3)	OT80W9TA	PON3_HUMAN	Increases Hydrolysis	[21]

Indication(s) of Dihydralazine

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[5]

Dihydralazine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[23]
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[24]

Dihydralazine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases ADR	[25]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[26]

References

• [1] ClinicalTrials.gov (NCT05230901) Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
• [2] Spironolactone 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: 2875).
• [4] Spironolactone in Covid-19 Induced ARDS
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
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• [10] A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor in an MCF-7 Microarray Compendium. Chem Res Toxicol. 2021 Feb 15;34(2):313-329. doi: 10.1021/acs.chemrestox.0c00243. Epub 2021 Jan 6.
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• [12] 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.
• [13] Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001 Apr;37(5):1228-33. doi: 10.1016/s0735-1097(01)01116-0.
• [14] Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression. Apoptosis. 2006 Apr;11(4):573-9. doi: 10.1007/s10495-006-4919-3.
• [15] Evaluation of an imaging-based in vitro screening platform for estrogenic activity with OECD reference chemicals. Toxicol In Vitro. 2022 Jun;81:105348. doi: 10.1016/j.tiv.2022.105348. Epub 2022 Mar 18.
• [16] Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology. 2011 Jul 11;285(1-2):18-24. doi: 10.1016/j.tox.2011.03.015. Epub 2011 Apr 1.
• [17] The human mineralocorticoid receptor only partially differentiates between different ligands after expression in fission yeast. FEMS Yeast Res. 2005 Apr;5(6-7):627-33. doi: 10.1016/j.femsyr.2004.12.007.
• [18] Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004 Feb 15;195(2-3):177-86. doi: 10.1016/j.tox.2003.09.012.
• [19] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [20] Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study. Hypertension. 1980 Sep-Oct;2(5):672-9. doi: 10.1161/01.hyp.2.5.672.
• [21] Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.
• [22] Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet. 2005;44(3):279-304.
• [23] Mechanism-based inactivation of cytochrome P450s 1A2 and 3A4 by dihydralazine in human liver microsomes. Chem Res Toxicol. 1999 Oct;12(10):1028-32.
• [24] The influence of the acetylator phenotype for the clinical use of dihydralazine. Int J Clin Pharmacol Ther Toxicol. 1985 Apr;23 Suppl 1:S74-8.
• [25] 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.
• [26] Additive effects of dihydralazine during enflurane or isoflurane hypotensive anaesthesia for spinal fusion. Can J Anaesth. 1988 May;35(3 ( Pt 1)):242-8. doi: 10.1007/BF03010617.