Details of the Drug Combination

General Information of Drug Combination (ID: DC4R3BG)

• Drug Combination Name: Amlodipine + Dobutamine
• Indication: Heart Failure With Preserved Ejection Fraction; Status: Phase 1 [1]
• Component Drugs:
  Amlodipine (DMBDAZV): Small molecular drug
  Dobutamine (DMD1B8Z): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amlodipine

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]
Stroke	8B20	Investigative	[2]

Amlodipine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated calcium channel alpha-2/delta-1 (CACNA2D1)	TTFK1JQ	CA2D1_HUMAN	Blocker	[5]

Amlodipine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]

Amlodipine Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Increases Expression	[7]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Response To Substance	[8]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[9]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[10]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[10]
Resistin (RETN)	OTW5Z1NH	RETN_HUMAN	Decreases Expression	[11]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases ADR	[12]

Indication(s) of Dobutamine

Disease Entry	ICD 11	Status	REF
Heart failure	BD10-BD13	Approved	[4]

Dobutamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[14]

Dobutamine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[15]

Dobutamine Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Affects Response To Substance	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[17]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[18]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[19]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[20]
Kallikrein-1 (KLK1)	OTFGP3UR	KLK1_HUMAN	Affects Response To Substance	[21]
Neuroendocrine secretory protein 55 (GNAS)	OTMH8BKJ	GNAS3_HUMAN	Increases Response To Substance	[22]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[23]

References

• [1] ClinicalTrials.gov (NCT01354613) Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)
• [2] Amlodipine 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: 6981).
• [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: 535).
• [5] A first drug combination for the treatment of arterial hypertension with a calcium channel antagonist (amlodipine besylate) and an angiotensin receptor blocker (valsartan): Exforge. Rev Med Liege. 2007 Nov;62(11):688-94.
• [6] Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014 Feb;42(2):245-9.
• [7] Amlodipine inhibits cell proliferation via PKD1-related pathway. Biochem Biophys Res Commun. 2008 May 2;369(2):376-81. doi: 10.1016/j.bbrc.2008.02.075. Epub 2008 Feb 25.
• [8] Effects of amlodipine on TGF--induced Smad2, 4 expressions in adriamycin toxicity of rat mesangial cells. Arch Toxicol. 2011 Jun;85(6):663-8. doi: 10.1007/s00204-011-0667-4. Epub 2011 Feb 20.
• [9] Platelet morphology and plasma indices of platelet activation in essential hypertension: effects of amlodipine-based antihypertensive therapy. Ann Med. 2004;36(7):552-7. doi: 10.1080/07853890410017386.
• [10] G1 cell cycle arrest by amlodipine, a dihydropyridine Ca2+ channel blocker, in human epidermoid carcinoma A431 cells. Biochem Pharmacol. 2007 Apr 1;73(7):943-53. doi: 10.1016/j.bcp.2006.12.011. Epub 2006 Dec 14.
• [11] Amlodipine improves endothelial function and metabolic parameters in patients with hypertension. Int J Cardiol. 2009 Mar 20;133(1):23-31. doi: 10.1016/j.ijcard.2007.11.058. Epub 2008 Jan 15.
• [12] Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. JAMA. 2008 Jan 23;299(3):296-307. doi: 10.1001/jama.299.3.296.
• [13] Gene therapy in cardiac surgery: intramyocardial injection of naked plasmid DNA for chronic myocardial ischemia. Eur J Cardiothorac Surg. 2003 Nov;24(5):785-93. doi: 10.1016/s1010-7940(03)00455-x.
• [14] Beta-adrenoceptor alterations coupled with secretory response and experimental periodontitis in rat submandibular glands. Arch Oral Biol. 2008 Jun;53(6):509-16.
• [15] Catechol-O-methyltransferase: substrate-specificity and stereoselectivity for beta-adrenoceptor agents. Xenobiotica. 1986 Jan;16(1):47-52.
• [16] The Arg389Gly 1-adrenoceptor gene polymorphism influences the acute effects of -adrenoceptor blockade on contractility in the human heart. Clin Res Cardiol. 2011 Aug;100(8):641-7. doi: 10.1007/s00392-011-0288-1. Epub 2011 Feb 11.
• [17] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [18] Beta-adrenoceptor activation-induced placental prorenin secretion is mediated by increased renin messenger RNA and protein synthesis. Mol Pharmacol. 1997 Feb;51(2):201-8. doi: 10.1124/mol.51.2.201.
• [19] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [20] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.
• [21] Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction. Hypertension. 2002 Nov;40(5):653-9. doi: 10.1161/01.hyp.0000036035.41122.99.
• [22] Effect of 393T>C polymorphism of GNAS1 gene on dobutamine response in Chinese healthy subjects. J Clin Pharmacol. 2009 Aug;49(8):929-36. doi: 10.1177/0091270009337945. Epub 2009 Jun 19.
• [23] A bivariate functional mapping model for identifying haplotypes that control drug response for systolic and diastolic blood pressures. Pac Symp Biocomput. 2006:572-83.