Details of the Drug

General Information of Drug (ID: DMYM974)

• Drug Name: Arformoterol
• Synonyms: 67346-49-0; Brovana; UNII-F91H02EBWT; Arformoterol tartrate; CHEMBL1363; F91H02EBWT; CHEBI:408174; Brovana (TN); Formoterol/fluticasone propionate

Indication

Disease Entry	ICD 11	Status	REF
Chronic obstructive pulmonary disease	CA22	Approved	[1]
Pulmonary emphysema	CA21.Z	Approved	[2]
Asthma	CA23	Phase 4	[3]

• Therapeutic Class: Bronchodilator Agents
• Affected Organisms: Humans and other mammals
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 344.4
  Logarithm of the Partition Coefficient (xlogp); 1.8
  Rotatable Bond Count (rotbonds); 8
  Hydrogen Bond Donor Count (hbonddonor); 4
  Hydrogen Bond Acceptor Count (hbondacc); 5
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [4]
  Clearance: The renal clearance of drug is 8.9 L/h []
  Elimination: 8% of drug is excreted from urine in the unchanged form [4]
  Half-life: The concentration or amount of drug in body reduced by one-half in 26 hours [5]
  Metabolism: The drug is metabolized via the cytochrome P450 enzym []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.001 micromolar/kg/day [6]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.66 mg/mL [4]
• Chemical Identifiers:
  Formula: C19H24N2O4
  IUPAC Name: N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide
  Canonical SMILES: C[C@H](CC1=CC=C(C=C1)OC)NC[C@@H](C2=CC(=C(C=C2)O)NC=O)O
  InChI: InChI=1S/C19H24N2O4/c1-13(9-14-3-6-16(25-2)7-4-14)20-11-19(24)15-5-8-18(23)17(10-15)21-12-22/h3-8,10,12-13,19-20,23-24H,9,11H2,1-2H3,(H,21,22)/t13-,19+/m1/s1
  InChIKey: BPZSYCZIITTYBL-YJYMSZOUSA-N
• Cross-matching ID:
  PubChem CID: 3083544
  ChEBI ID: CHEBI:408174
  CAS Number: 67346-49-0
  UNII: F91H02EBWT
  DrugBank ID: DB01274
  TTD ID: D0D1DI
  INTEDE ID: DR0131
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Agonist	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2D6 (CYP2D6) Main DME	DECB0K3	CP2D6_HUMAN	Substrate	[8]
Mephenytoin 4-hydroxylase (CYP2C19) Main DME	DEGTFWK	CP2CJ_HUMAN	Substrate	[8]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Substrate	[8]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Gene/Protein Processing	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Gene/Protein Processing	[10]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Gene/Protein Processing	[11]
Eosinophil cationic protein (RNASE3)	OTVE2XD1	ECP_HUMAN	Gene/Protein Processing	[12]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Gene/Protein Processing	[13]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Regulation of Drug Effects	[14]

Molecular Expression Atlas of This Drug

• ICD Disease Classification: 12 Disease of the respiratory system
• Disease Class: ICD-11: CA23 Asthma
• The Studied Tissue: Lung tissue
• The Studied Disease: Chronic obstructive pulmonary disease [ICD-11:CA23]

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Adrenergic receptor beta-2 (ADRB2)	DTT	ADRB2	4.88E-01	-0.05	-0.12
Adrenergic receptor beta-2 (ADRB2)	DTT	ADRB2	7.10E-01	0.06	0.09
Cytochrome P450 2A6 (CYP2A6)	DME	CYP2A6	4.70E-01	2.63E-01	6.12E-01
Cytochrome P450 2A6 (CYP2A6)	DME	CYP2A6	1.35E-03	-2.46E-01	-5.85E-01
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	4.79E-03	1.32E-01	7.85E-01
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	1.82E-01	-1.71E-02	-9.86E-02
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	8.01E-02	6.73E-02	3.36E-01
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	2.91E-04	1.41E-01	6.14E-01

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Arformoterol (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Methylene blue	DMJAPE7	Moderate	Additive hypertensive effects by the combination of Arformoterol and Methylene blue.	Acquired methaemoglobinaemia [3A93]	[15]
Ivosidenib	DM8S6T7	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Ivosidenib.	Acute myeloid leukaemia [2A60]	[16]
Midostaurin	DMI6E0R	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Midostaurin.	Acute myeloid leukaemia [2A60]	[16]
Arn-509	DMT81LZ	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Arn-509.	Acute myeloid leukaemia [2A60]	[16]
Gilteritinib	DMTI0ZO	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Gilteritinib.	Acute myeloid leukaemia [2A60]	[16]
Oliceridine	DM6MDCF	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Oliceridine.	Acute pain [MG31]	[16]
Ivabradine	DM0L594	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Ivabradine.	Angina pectoris [BA40]	[16]
Dronedarone	DMA8FS5	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Dronedarone.	Angina pectoris [BA40]	[16]
Bedaquiline	DM3906J	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Bedaquiline.	Antimicrobial drug resistance [MG50-MG52]	[16]
Droxidopa	DM5YF4M	Moderate	Additive hypertensive effects by the combination of Arformoterol and Droxidopa.	Autonomic nervous system disorder [8D87]	[17]
Retigabine	DMGNYIH	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Retigabine.	Behcet disease [4A62]	[16]
Eribulin	DM1DX4Q	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Eribulin.	Breast cancer [2C60-2C6Y]	[16]
Bosutinib	DMTI8YE	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Bosutinib.	Breast cancer [2C60-2C6Y]	[16]
Corticotropin	DMP9TWZ	Minor	Increased risk of hypokalemia by the combination of Arformoterol and Corticotropin.	Chronic kidney disease [GB61]	[18]
PF-04449913	DMSB068	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and PF-04449913.	Chronic myelomonocytic leukaemia [2A40]	[16]
Levomilnacipran	DMV26S8	Moderate	Increased risk of rapid heart rate by the combination of Arformoterol and Levomilnacipran.	Chronic pain [MG30]	[19]
Probucol	DMVZQ2M	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Probucol.	Coronary atherosclerosis [BA80]	[16]
Pasireotide	DMHM7JS	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Pasireotide.	Cushing syndrome [5A70]	[16]
Osilodrostat	DMIJC9X	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Osilodrostat.	Cushing syndrome [5A70]	[16]
Milnacipran	DMBFE74	Moderate	Increased risk of rapid heart rate by the combination of Arformoterol and Milnacipran.	Depression [6A70-6A7Z]	[19]
Desvenlafaxine	DMHD4PE	Moderate	Additive hypertensive effects by the combination of Arformoterol and Desvenlafaxine.	Depression [6A70-6A7Z]	[19]
Tetrabenazine	DMYWQ0O	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Tetrabenazine.	Dissociative neurological symptom disorder [6B60]	[16]
Deutetrabenazine	DMUPFLI	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Deutetrabenazine.	Dystonic disorder [8A02]	[16]
Ingrezza	DMVPLNC	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Ingrezza.	Dystonic disorder [8A02]	[16]
Solifenacin	DMG592Q	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Solifenacin.	Functional bladder disorder [GC50]	[16]
Fostemsavir	DM50ILT	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Fostemsavir.	Human immunodeficiency virus disease [1C60-1C62]	[16]
Lopinavir	DMITQS0	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Lopinavir.	Human immunodeficiency virus disease [1C60-1C62]	[20]
Rilpivirine	DMJ0QOW	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Rilpivirine.	Human immunodeficiency virus disease [1C60-1C62]	[16]
Crizotinib	DM4F29C	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Crizotinib.	Lung cancer [2C25]	[16]
Ceritinib	DMB920Z	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Ceritinib.	Lung cancer [2C25]	[16]
Osimertinib	DMRJLAT	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Osimertinib.	Lung cancer [2C25]	[16]
Selpercatinib	DMZR15V	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Selpercatinib.	Lung cancer [2C25]	[16]
Lumefantrine	DM29GAD	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Lumefantrine.	Malaria [1F40-1F45]	[20]
Inotuzumab ozogamicin	DMAC130	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Inotuzumab ozogamicin.	Malignant haematopoietic neoplasm [2B33]	[16]
Vemurafenib	DM62UG5	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Vemurafenib.	Melanoma [2C30]	[16]
LGX818	DMNQXV8	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and LGX818.	Melanoma [2C30]	[16]
Panobinostat	DM58WKG	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Panobinostat.	Multiple myeloma [2A83]	[16]
Siponimod	DM2R86O	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Siponimod.	Multiple sclerosis [8A40]	[16]
Fingolimod	DM5JVAN	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Fingolimod.	Multiple sclerosis [8A40]	[16]
Ozanimod	DMT6AM2	Major	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Ozanimod.	Multiple sclerosis [8A40]	[21]
Romidepsin	DMT5GNL	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Romidepsin.	Mycosis fungoides [2B01]	[16]
Nilotinib	DM7HXWT	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Nilotinib.	Myeloproliferative neoplasm [2A20]	[16]
Entrectinib	DMMPTLH	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Entrectinib.	Non-small cell lung cancer [2C25]	[16]
Rucaparib	DM9PVX8	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Rucaparib.	Ovarian cancer [2C73]	[16]
Triclabendazole	DMPWGBR	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Triclabendazole.	Parasitic worm infestation [1F90]	[16]
Safinamide	DM0YWJC	Moderate	Additive hypertensive effects by the combination of Arformoterol and Safinamide.	Parkinsonism [8A00]	[15]
Rasagiline	DM3WKQ4	Moderate	Additive hypertensive effects by the combination of Arformoterol and Rasagiline.	Parkinsonism [8A00]	[15]
Pimavanserin	DMR7IVC	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Pimavanserin.	Parkinsonism [8A00]	[16]
Macimorelin	DMQYJIR	Major	Increased risk of prolong QT interval by the combination of Arformoterol and Macimorelin.	Pituitary gland disorder [5A60-5A61]	[22]
Lefamulin	DME6G97	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Lefamulin.	Pneumonia [CA40]	[16]
Degarelix	DM3O8QY	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Degarelix.	Prostate cancer [2C82]	[16]
ABIRATERONE	DM8V75C	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and ABIRATERONE.	Prostate cancer [2C82]	[16]
Enzalutamide	DMGL19D	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Enzalutamide.	Prostate cancer [2C82]	[16]
Levomepromazine	DMIKFEL	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Levomepromazine.	Psychotic disorder [6A20-6A25]	[16]
Ciclesonide	DM2NA4K	Minor	Increased risk of hypokalemia by the combination of Arformoterol and Ciclesonide.	Respiratory system disease [CB40-CB7Z]	[18]
Iloperidone	DM6AUFY	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Iloperidone.	Schizophrenia [6A20]	[16]
Amisulpride	DMSJVAM	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Amisulpride.	Schizophrenia [6A20]	[16]
Asenapine	DMSQZE2	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Asenapine.	Schizophrenia [6A20]	[16]
LEE011	DMMX75K	Major	Increased risk of prolong QT interval by the combination of Arformoterol and LEE011.	Solid tumour/cancer [2A00-2F9Z]	[23]
Vandetanib	DMRICNP	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Vandetanib.	Solid tumour/cancer [2A00-2F9Z]	[16]
Triptorelin	DMTK4LS	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Triptorelin.	Solid tumour/cancer [2A00-2F9Z]	[16]
Pitolisant	DM8RFNJ	Moderate	Increased risk of prolong QT interval by the combination of Arformoterol and Pitolisant.	Somnolence [MG42]	[16]
Telavancin	DM58VQX	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Telavancin.	Staphylococcal/streptococcal disease [1B5Y]	[16]
Lenvatinib	DMB1IU4	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Lenvatinib.	Thyroid cancer [2D10]	[16]
Cabozantinib	DMIYDT4	Moderate	Increased risk of ventricular arrhythmias by the combination of Arformoterol and Cabozantinib.	Thyroid cancer [2D10]	[16]
Fluticasone	DMGCSVF	Minor	Increased risk of hypokalemia by the combination of Arformoterol and Fluticasone.	Vasomotor/allergic rhinitis [CA08]	[18]

References

• [1] 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: 7479).
• [2] Arformoterol FDA Label
• [3] ClinicalTrials.gov (NCT02491970) Study to Evaluate Small Airway Parameters of Fluticasone/Formoterol (Flutiform) Compared to Fluticasone/Salmeterol in Asthma Patients.
• [4] BDDCS applied to over 900 drugs
• [5] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [6] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [7] Arformoterol tartrate in the treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease. Drugs Today (Barc). 2009 Jan;45(1):3-9.
• [8] A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007 Oct;35(10):1797-805.
• [9] The 2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts. Naunyn Schmiedebergs Arch Pharmacol. 2011 Aug;384(2):133-45. doi: 10.1007/s00210-011-0655-5. Epub 2011 May 21.
• [10] Long-acting beta2-adrenergic formoterol and salmeterol induce the apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 2004 Jan;124(2):141-50. doi: 10.1046/j.1365-2141.2003.04746.x.
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• [14] The effect of corticosteroids on the disposal of long-acting beta2-agonists by airway smooth muscle cells. J Allergy Clin Immunol. 2007 Nov;120(5):1103-9. doi: 10.1016/j.jaci.2007.08.034. Epub 2007 Oct 17.
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• [19] Product Information. Cymbalta (duloxetine). Lilly, Eli and Company, Indianapolis, IN.
• [20] Product Information. Arcapta Neohaler (indacaterol). Novartis Pharmaceuticals, East Hanover, NJ.
• [21] Product Information. Zeposia (ozanimod). Celgene Corporation, Summit, NJ.
• [22] Product Information. Macrilen (macimorelin). Aeterna Zentaris, Charleston, SC.
• [23] Canadian Pharmacists Association.