Details of the Drug Combination

General Information of Drug Combination (ID: DC7NVJH)

• Drug Combination Name: Metoprolol + Enoximone
• Indication: Heart Failure, Congestive; Status: Phase 1 [1]
• Component Drugs:
  Metoprolol (DMOJ0V6): Small molecular drug
  Enoximone (DMQVZJD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metoprolol

Disease Entry	ICD 11	Status	REF
Acute coronary syndrome	BA41	Approved	[2]
Angina pectoris	BA40	Approved	[2]
Cardiac arrest	MC82	Approved	[2]
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]
Myocardial infarction	BA41-BA43	Approved	[2]
Obesity	5B81	Approved	[2]
Ventricular fibrillation	BC71.1	Approved	[2]

Metoprolol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Antagonist	[6]

Metoprolol Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[7]

Metoprolol Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]

Metoprolol Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Hydroxylation	[11]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[12]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[5]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[5]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[5]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Expression	[13]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Increases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[15]
Endothelin-converting enzyme 1 (ECE1)	OTPFHC6F	ECE1_HUMAN	Decreases Expression	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[17]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Activity	[18]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Affects Response To Substance	[19]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[20]
G protein-coupled receptor kinase 4 (GRK4)	OTUU8V2S	GRK4_HUMAN	Affects Response To Substance	[21]

Indication(s) of Enoximone

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

Enoximone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 3 (PDE3)	TTZCG4L	NOUNIPROTAC	Modulator	[22]
Phosphodiesterase 3A (PDE3A)	TT06AWU	PDE3A_HUMAN	Inhibitor	[23]

References

• [1] ClinicalTrials.gov (NCT00077948) Enoximone Plus Extended-Release Metoprolol Succinate in Subjects With Advanced Chronic Heart Failure
• [2] Metoprolol 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: 553).
• [4] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [5] beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFB and AP-1. Cancer Biol Ther. 2010 Jul 1;10(1):19-29.
• [6] Prediction and experimental validation of acute toxicity of beta-blockers in Ceriodaphnia dubia. Environ Toxicol Chem. 2005 Oct;24(10):2470-6.
• [7] 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.
• [8] Chemical stability-indicating HPLC study of fixed-dosage combination containing metoprolol tartrate and hydrochlorothiazide.
• [9] The impact of CYP2D6 mediated drug-drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine. Br J Clin Pharmacol. 2018 Dec;84(12):2704-2715.
• [10] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [11] Cytochrome P450 enzymes involved in metoprolol metabolism and use of metoprolol as a CYP2D6 phenotyping probe drug. Front Pharmacol. 2018 Jul 24;9:774.
• [12] Major differences in gene expression in human coronary smooth muscle cells after nebivolol or metoprolol treatment. Int J Cardiol. 2008 Mar 28;125(1):4-10.
• [13] Effect of carvedilol and metoprolol on blood pressure, blood flow, and vascular resistance. J Cardiovasc Pharmacol. 1987;10 Suppl 11:S124-9.
• [14] Modelling cardiac fibrosis using three-dimensional cardiac microtissues derived from human embryonic stem cells. J Biol Eng. 2019 Feb 13;13:15. doi: 10.1186/s13036-019-0139-6. eCollection 2019.
• [15] Inhibition of pancreatic cancer cell proliferation by propranolol occurs through apoptosis induction: the study of beta-adrenoceptor antagonist's anticancer effect in pancreatic cancer cell. Pancreas. 2009 Jan;38(1):94-100. doi: 10.1097/MPA.0b013e318184f50c.
• [16] Endothelin converting-enzyme-1 mRNA expression in human cardiovascular disease. Clin Exp Hypertens. 1998 May;20(4):417-37. doi: 10.3109/10641969809053222.
• [17] Comparison of HERG channel blocking effects of various beta-blockers-- implication for clinical strategy. Br J Pharmacol. 2006 Mar;147(6):642-52. doi: 10.1038/sj.bjp.0706508.
• [18] Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation. 2003 May 20;107(19):2459-66. doi: 10.1161/01.CIR.0000068316.53218.49. Epub 2003 May 12.
• [19] Angiotensin-converting enzyme gene I/D genotype affected metoprolol-induced reduction in 24-hour average heart rate. Chin Med J (Engl). 2010 Jun;123(11):1382-6.
• [20] Beta-2-adrenergic receptor polymorphisms and changes in lipids induced by metoprolol. Pharmacology. 2007;80(4):279-85. doi: 10.1159/000106554. Epub 2007 Aug 2.
• [21] G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions. Am J Hypertens. 2009 Mar;22(3):332-8. doi: 10.1038/ajh.2008.341. Epub 2009 Jan 1.
• [22] In vitro and in vivo effects of the phosphodiesterase-III inhibitor enoximone on malignant hyperthermia-susceptible swine. Anesthesiology. 2003 Apr;98(4):944-9.
• [23] Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin... J Med Chem. 1987 Feb;30(2):303-18.