Details of the Drug Combination

General Information of Drug Combination (ID: DCYZFC5)

• Drug Combination Name: Salmeterol + Fluticasone propionate
• Indication: Allergic Asthma; Status: Phase 1 [1]
• Component Drugs:
  Salmeterol (DMIEU69): Small molecular drug
  Fluticasone propionate (DMRWLB2): N.A.

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	[5]

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	[6]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[7]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[7]

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	[8]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[9]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Affects Localization	[10]
Non-secretory ribonuclease (RNASE2)	OT8Z4FNE	RNAS2_HUMAN	Decreases Expression	[11]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Eosinophil cationic protein (RNASE3)	OTVE2XD1	ECP_HUMAN	Decreases Expression	[13]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Expression	[14]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[15]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[16]

Indication(s) of Fluticasone propionate

Disease Entry	ICD 11	Status	REF
Allergic asthma	CA23.0	Approved	[4]
Allergic rhinitis	CA08.0	Approved	[4]
Bronchiolitis	N.A.	Approved	[4]
Exanthem	N.A.	Approved	[4]
Granuloma annulare	N.A.	Approved	[4]
Intrinsic asthma	N.A.	Approved	[4]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[4]
Pulmonary emphysema	CA21.Z	Approved	[4]

Fluticasone propionate Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]

Fluticasone propionate Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Secretion	[19]
Glutathione hydrolase 5 proenzyme (GGT5)	OTDJYEO7	GGT5_HUMAN	Increases Expression	[20]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[21]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[22]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[23]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Increases Expression	[24]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[10]
Annexin A1 (ANXA1)	OT5OFDJC	ANXA1_HUMAN	Affects Localization	[25]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[26]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Affects Localization	[10]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[27]
Protein kinase C alpha type (PRKCA)	OT5UWNRD	KPCA_HUMAN	Decreases Expression	[27]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Activity	[28]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Increases Expression	[10]
Cytosolic phospholipase A2 (PLA2G4A)	OTE70SOT	PA24A_HUMAN	Affects Localization	[25]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Asthma	DCU6QC9	N. A.	Approved	[29]

References

• [1] ClinicalTrials.gov (NCT00214019) The Effect of Salmeterol on Eosinophil (EOS) Function
• [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] Fluticasone propionate FDA Label
• [5] Pharmacogenetic tests in asthma therapy. Clin Lab Med. 2008 Dec;28(4):645-65.
• [6] Clinical pharmacokinetics of salmeterol. Clin Pharmacokinet. 2002;41(1):19-30.
• [7] Drug Interactions Flockhart Table
• [8] 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.
• [9] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Inhibition of VCAM-1 expression in human bronchial epithelial cells by glucocorticoids. Am J Respir Cell Mol Biol. 1999 Apr;20(4):643-50. doi: 10.1165/ajrcmb.20.4.3265.
• [18] Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012 May 1;260(3):294-302.
• [19] Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012 May 1;260(3):294-302. doi: 10.1016/j.taap.2012.03.008. Epub 2012 Mar 23.
• [20] A novel pharmacologic action of glucocorticosteroids on leukotriene C4 catabolism. J Allergy Clin Immunol. 2001 Jul;108(1):122-4.
• [21] The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 enzyme. Chem Res Toxicol. 2010 Aug 16;23(8):1356-64.
• [22] Regulation of CYP3A genes by glucocorticoids in human lung cells. F1000Res. 2013 Aug 13;2:173.
• [23] Identification and validation of novel human pregnane X receptor activators among prescribed drugs via ligand-based virtual screening. Drug Metab Dispos. 2011 Feb;39(2):337-44. doi: 10.1124/dmd.110.035808. Epub 2010 Nov 10.
• [24] Improved safety with equivalent asthma control in adults with chronic severe asthma on high-dose fluticasone propionate. Respirology. 2001 Sep;6(3):237-46. doi: 10.1046/j.1440-1843.2001.00329.x.
• [25] Glucocorticoid-induced surface expression of annexin 1 blocks beta2-integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein. J Allergy Clin Immunol. 2005 Mar;115(3):493-500. doi: 10.1016/j.jaci.2004.11.010.
• [26] Inhibition of GM-CSF secretion by topical corticosteroids and nedocromil sodium. A comparison study using nasal polyp epithelial cells. Respir Med. 2000 May;94(5):428-31. doi: 10.1053/rmed.1999.0756.
• [27] [The effect of inhaled glucocorticosteroid on protein kinase C alpha expression and interleukin-5 production in induced sputum inflammatory cells of asthma patients]. Zhonghua Nei Ke Za Zhi. 2004 Nov;43(11):849-52.
• [28] Association of human serum paraoxonase-1 with some respiratory drugs. J Biochem Mol Toxicol. 2019 Dec;33(12):e22407. doi: 10.1002/jbt.22407. Epub 2019 Oct 3.
• [29] UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2017 Jan 4;45(D1):D158-D169. (ID: O95477)