Details of the Drug Combination

General Information of Drug Combination (ID: DC5LFA0)

• Drug Combination Name: Salmeterol + Formoterol
• Indication: Asthma; Status: Phase 1 [1]
• Component Drugs:
  Salmeterol (DMIEU69): Small molecular drug
  Formoterol (DMSOURV): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Salmeterol

Disease Entry	ICD 11	Status	REF
Allergic asthma	CA23.0	Approved	[2]
Chronic obstructive pulmonary disease	CA22	Approved	[3]
Intrinsic asthma	N.A.	Approved	[2]
Pulmonary emphysema	CA21.Z	Approved	[2]

Salmeterol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Agonist	[6]

Salmeterol Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[8]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[8]

Salmeterol Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Expression	[9]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[10]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Affects Localization	[11]
Non-secretory ribonuclease (RNASE2)	OT8Z4FNE	RNAS2_HUMAN	Decreases Expression	[12]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Eosinophil cationic protein (RNASE3)	OTVE2XD1	ECP_HUMAN	Decreases Expression	[14]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Expression	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[16]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[17]

Indication(s) of Formoterol

Disease Entry	ICD 11	Status	REF
Allergic asthma	CA23.0	Approved	[4]
Asthma	CA23	Approved	[5]
Intrinsic asthma	N.A.	Approved	[4]
Pulmonary emphysema	CA21.Z	Approved	[4]

Formoterol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Agonist	[18]

Formoterol Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[19]

Formoterol Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[20]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[20]

Formoterol Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Increases ADR	[22]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases ADR	[22]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Increases ADR	[22]

References

• [1] ClinicalTrials.gov (NCT01290874) Blacks and Exacerbations on Long Acting Beta Agonists (LABA) vs. Tiotropium (BELT)
• [2] Salmeterol 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: 559).
• [4] Formoterol FDA Label
• [5] 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: 3465).
• [6] Pharmacogenetic tests in asthma therapy. Clin Lab Med. 2008 Dec;28(4):645-65.
• [7] Clinical pharmacokinetics of salmeterol. Clin Pharmacokinet. 2002;41(1):19-30.
• [8] Drug Interactions Flockhart Table
• [9] Pleiotropic beta-agonist-promoted receptor conformations and signals independent of intrinsic activity. Am J Respir Cell Mol Biol. 2007 Feb;36(2):236-43. doi: 10.1165/rcmb.2006-0257OC. Epub 2006 Sep 15.
• [10] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [11] Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. Am J Respir Crit Care Med. 2005 Sep 15;172(6):704-12. doi: 10.1164/rccm.200408-1041OC. Epub 2005 Apr 28.
• [12] Comparison of anti-inflammatory and clinical effects of beclomethasone dipropionate and salmeterol in moderate asthma. Eur Respir J. 2002 Jul;20(1):66-72. doi: 10.1183/09031936.02.00094202.
• [13] 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.
• [14] Salmeterol decreases eosinophilic cationic protein and rescue medication in patients inhaling beclomethasone dipropionate: preliminary study in mild and moderate asthma in Trinidad, West Indies. Int J Clin Pharmacol Res. 2003;23(2-3):69-74.
• [15] Stimulation of beta 2-adrenergic receptor increases cystic fibrosis transmembrane conductance regulator expression in human airway epithelial cells through a cAMP/protein kinase A-independent pathway. J Biol Chem. 2003 May 9;278(19):17320-7. doi: 10.1074/jbc.M212227200. Epub 2003 Mar 5.
• [16] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [17] 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.
• [18] Long-acting beta2-agonists for chronic obstructive pulmonary disease patients with poorly reversible airflow limitation. Cochrane Database Syst Rev. 2002;(3):CD001104.
• [19] 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.
• [20] 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.
• [21] FDA Label of Formoterol. The 2020 official website of the U.S. Food and Drug Administration.
• [22] 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.