Details of the Drug Combination

General Information of Drug Combination (ID: DCUOH4Z)

• Drug Combination Name: Beclomethasone dipropionate + Fluticasone
• Indication: Asthma; Status: Phase 1 [1]
• Component Drugs:
  Beclomethasone dipropionate (DM5NW1E): N.A.
  Fluticasone (DMGCSVF): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Beclomethasone dipropionate

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[2]
Nasal polyp	CA0J	Approved	[2]
Rhinitis	FA20	Approved	[2]
Vasomotor/allergic rhinitis	CA08	Approved	[2]
Asthma	CA23	Investigative	[2]

Beclomethasone dipropionate Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Beclomethasone dipropionate Interacts with 42 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[4]
Tartrate-resistant acid phosphatase type 5 (ACP5)	OTBV4498	PPA5_HUMAN	Decreases Activity	[7]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Increases Expression	[8]
Glutathione hydrolase 5 proenzyme (GGT5)	OTDJYEO7	GGT5_HUMAN	Increases Expression	[9]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[10]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Expression	[11]
Cytosolic phospholipase A2 (PLA2G4A)	OTE70SOT	PA24A_HUMAN	Decreases Activity	[12]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Increases Expression	[4]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Increases Expression	[4]
Cytochrome P450 2S1 (CYP2S1)	OTKHX4RF	CP2S1_HUMAN	Decreases Expression	[13]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Expression	[14]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[15]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Increases Expression	[16]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Expression	[17]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[18]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[19]
Interleukin-2 receptor subunit alpha (IL2RA)	OT0MWCHG	IL2RA_HUMAN	Decreases Expression	[20]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Decreases Secretion	[21]
Lactotransferrin (LTF)	OT8JWCZ0	TRFL_HUMAN	Decreases Secretion	[22]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Decreases Expression	[23]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[24]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[25]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[26]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Expression	[27]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[28]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Decreases Activity	[29]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[30]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[5]
Non-secretory ribonuclease (RNASE2)	OT8Z4FNE	RNAS2_HUMAN	Decreases Expression	[31]
Eosinophil cationic protein (RNASE3)	OTVE2XD1	ECP_HUMAN	Decreases Expression	[32]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[5]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[5]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[33]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[16]
Interleukin-1 receptor antagonist protein (IL1RN)	OT308CBE	IL1RA_HUMAN	Decreases Expression	[30]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[18]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Increases Activity	[34]
B1 bradykinin receptor (BDKRB1)	OT1DHSVQ	BKRB1_HUMAN	Decreases Expression	[35]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[36]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Activity	[37]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Increases Metabolism	[38]
Pyrin (MEFV)	OTRJ6S6K	MEFV_HUMAN	Increases Response To Substance	[39]

Indication(s) of Fluticasone

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[3]

Fluticasone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor (NR3C1)	TTYRL6O	GCR_HUMAN	Antagonist	[40]

Fluticasone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[41]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[41]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[42]

References

• [1] ClinicalTrials.gov (NCT01741285) Effects of QVAR in Smokers With Asthma
• [2] Beclomethasone dipropionate FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Induction of drug-metabolizing enzymes and transporters in human bronchial epithelial cells by beclomethasone dipropionate. IUBMB Life. 2004 Jun;56(6):355-9.
• [5] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [6] Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012 May 1;260(3):294-302.
• [7] Bone metabolism in children with asthma treated with inhaled beclomethasone dipropionate. J Pediatr. 1993 Feb;122(2):219-26.
• [8] Changes in levels of catalase and glutathione in erythrocytes of patients with stable asthma, treated with beclomethasone dipropionate. Eur Respir J. 1999 Jun;13(6):1260-6.
• [9] A novel pharmacologic action of glucocorticosteroids on leukotriene C4 catabolism. J Allergy Clin Immunol. 2001 Jul;108(1):122-4.
• [10] Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther. 2003 Feb;304(2):745-52.
• [11] Correlation between change in pulmonary function and suppression of reactive nitrogen species production following steroid treatment in COPD. Thorax. 2003 Apr;58(4):299-305.
• [12] Comparison of in vitro-activity of commonly used topical glucocorticoids on cytokine- and phospholipase inhibition. Eur J Med Res. 2004 Aug 31;9(8):383-90.
• [13] CYP2S1 is negatively regulated by corticosteroids in human cell lines. Toxicol Lett. 2012 Feb 25;209(1):30-4.
• [14] Regulation of CYP3A genes by glucocorticoids in human lung cells. F1000Res. 2013 Aug 13;2:173.
• [15] 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.
• [16] Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma. J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):356-63. doi: 10.1016/s0091-6749(99)70379-9.
• [17] Glucocorticoids decrease c-fos expression in human nasal polyps in vivo. Thorax. 1998 Jul;53(7):577-82. doi: 10.1136/thx.53.7.577.
• [18] Phosphodiesterase type 4 inhibitors, but not glucocorticoids, are more potent in suppression of cytokine secretion by mononuclear cells from atopic than nonatopic donors. J Allergy Clin Immunol. 1998 Nov;102(5):797-804. doi: 10.1016/s0091-6749(98)70020-x.
• [19] Effect of inhaled glucocorticoids on IL-1 beta and IL-1 receptor antagonist (IL-1 ra) expression in asthmatic bronchial epithelium. Thorax. 1997 May;52(5):407-10. doi: 10.1136/thx.52.5.407.
• [20] Inhaled beclomethasone dipropionate downregulates airway lymphocyte activation in atopic asthma. Am J Respir Crit Care Med. 1994 Jan;149(1):86-90. doi: 10.1164/ajrccm.149.1.8111605.
• [21] The role of IFN-gamma in regulation of IFN-gamma-inducible protein 10 (IP-10) expression in lung epithelial cell and peripheral blood mononuclear cell co-cultures. Respir Res. 2007 Nov 8;8(1):80. doi: 10.1186/1465-9921-8-80.
• [22] Effects of topical glucocorticoids on in vitro lactoferrin glandular secretion: comparison between human upper and lower airways. J Allergy Clin Immunol. 2000 Dec;106(6):1053-62. doi: 10.1067/mai.2000.110476.
• [23] A large volume spacer significantly reduces the effect of inhaled steroids on bone formation. Postgrad Med J. 1995 Mar;71(833):156-9. doi: 10.1136/pgmj.71.833.156.
• [24] 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.
• [25] Differential potency of beclomethasone esters in-vitro on human T-lymphocyte cytokine production and osteoblast activity. J Pharm Pharmacol. 2000 Apr;52(4):417-23. doi: 10.1211/0022357001774174.
• [26] Expression of the prostate specific antigen gene by lung tissue. Clin Cancer Res. 1997 Jul;3(7):1201-6.
• [27] Biochemical interaction between effects of beclomethasone dipropionate and salbutamol or formoterol in sputum cells from mild to moderate asthmatics. Allergy. 2005 Mar;60(3):323-9. doi: 10.1111/j.1398-9995.2005.00702.x.
• [28] Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol. 2004 Sep;151(3):397-406. doi: 10.1530/eje.0.1510397.
• [29] Anti-proliferative and anti-remodelling effect of beclomethasone dipropionate, formoterol and salbutamol alone or in combination in primary human bronchial fibroblasts. Allergy. 2008 Apr;63(4):432-7. doi: 10.1111/j.1398-9995.2007.01582.x. Epub 2007 Dec 8.
• [30] Effects of early inhaled beclomethasone therapy on tracheal aspirate inflammatory mediators IL-8 and IL-1ra in ventilated preterm infants at risk for bronchopulmonary dysplasia. Pediatr Pulmonol. 2000 Oct;30(4):275-81. doi: 10.1002/1099-0496(200010)30:4<275::aid-ppul1>3.0.co;2-g.
• [31] 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.
• [32] Effect of inhaled beclomethasone dipropionate and budesonide dry powder on pulmonary function and serum eosinophil cationic protein in adult asthmatics. J Investig Allergol Clin Immunol. 1999 Jul-Aug;9(4):241-7.
• [33] Expression of RANTES by human bronchial epithelial cells in vitro and in vivo and the effect of corticosteroids. Am J Respir Cell Mol Biol. 1996 Jan;14(1):27-35. doi: 10.1165/ajrcmb.14.1.8534483.
• [34] [Effects of beclomethasone dipropionate and budesonide on interleukin-13 induced cytokine release, proliferation and differentiation of the human lung fibroblasts]. Zhonghua Jie He He Hu Xi Za Zhi. 2007 Aug;30(8):599-604.
• [35] Comparison of kinin B(1) and B(2) receptor expression in neutrophils of asthmatic and non-asthmatic subjects. Int Immunopharmacol. 2007 Dec 20;7(14):1862-8. doi: 10.1016/j.intimp.2007.07.012. Epub 2007 Aug 6.
• [36] Apoptosis of airway epithelial cells induced by corticosteroids. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1939-47. doi: 10.1164/ajrccm.164.10.2103013.
• [37] Modulation of p-glycoprotein and breast cancer resistance protein by some prescribed corticosteroids. Eur J Pharmacol. 2006 Feb 15;531(1-3):25-33. doi: 10.1016/j.ejphar.2005.12.010. Epub 2006 Jan 25.
• [38] Metabolism of synthetic steroids by the human placenta. Placenta. 2007 Jan;28(1):39-46.
• [39] The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011 Apr;40(5):467-72. doi: 10.1016/j.semarthrit.2010.06.009. Epub 2010 Sep 9.
• [40] Fluticasone furoate nasal spray in allergic rhinitis. Drugs Today (Barc). 2008 Apr;44(4):251-60.
• [41] Regulation of drug-metabolizing cytochrome P450 enzymes by glucocorticoids. Drug Metab Rev. 2010 Nov;42(4):621-35.
• [42] Biotransformation of fluticasone: in vitro characterization. Drug Metab Dispos. 2006 Jun;34(6):1035-40.