Details of the Drug Combination

General Information of Drug Combination (ID: DCKY9IF)

• Drug Combination Name: Salbutamol + Roflumilast
• Indication: COPD; Status: Phase 1 [1]
• Component Drugs:
  Salbutamol (DMN9CWF): Small molecular drug
  Roflumilast (DMPGHY8): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Salbutamol

Disease Entry	ICD 11	Status	REF
Acute asthma	CA23	Approved	[2]
Adult respiratory distress syndrome	CB00	Approved	[3]
Severe asthma	CA23	Approved	[4]

Salbutamol 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	[7]

Salbutamol 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	[8]

Salbutamol Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[10]
Sulfotransferase 1A3 (SULT1A3)	DEP7E8X	ST1A3_HUMAN	Metabolism	[11]

Salbutamol Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Response To Substance	[12]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Increases Expression	[13]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Increases Expression	[14]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[15]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[16]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[17]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[17]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Decreases Expression	[17]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[18]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[19]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[20]
Creatine kinase M-type (CKM)	OTME0KO7	KCRM_HUMAN	Increases Secretion	[21]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[18]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Increases Expression	[19]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Increases Expression	[19]
Platelet-activating factor receptor (PTAFR)	OT2133DF	PTAFR_HUMAN	Increases Expression	[19]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[19]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Activity	[22]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[17]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[18]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[17]
Hepatic sodium/bile acid cotransporter (SLC10A1)	OTUJVMCL	NTCP_HUMAN	Increases Expression	[14]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[17]
Low-density lipoprotein receptor (LDLR)	OTH559LU	LDLR_HUMAN	Affects Response To Substance	[23]

Indication(s) of Roflumilast

Disease Entry	ICD 11	Status	REF
Asthma	CA23	Approved	[5]
Type-2 diabetes	5A11	Phase 1	[6]
Chronic obstructive pulmonary disease	CA22	Withdrawn from market	[5]
Atopic dermatitis	EA80	Discontinued in Phase 2	[5]

Roflumilast Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 4 (PDE4)	TTV5CGO	NOUNIPROTAC	Modulator	[24]

Roflumilast Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[25]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[25]

Roflumilast Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B)	OT4217NK	PDE8B_HUMAN	Decreases Activity	[26]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[27]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[27]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[27]
3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A)	OTMUUZLF	PDE4A_HUMAN	Decreases Activity	[26]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[27]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[27]
3',5'-cyclic-AMP phosphodiesterase 4B (PDE4B)	OTOA8WU2	PDE4B_HUMAN	Decreases Activity	[26]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[27]
3',5'-cyclic-AMP phosphodiesterase 4C (PDE4C)	OTI8VMHZ	PDE4C_HUMAN	Decreases Activity	[26]
3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D)	OT1RWFV0	PDE4D_HUMAN	Decreases Activity	[26]
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (PDE3B)	OT1GI1TE	PDE3B_HUMAN	Decreases Activity	[26]
High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A)	OTVDV4IT	PDE7A_HUMAN	Decreases Activity	[26]
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A)	OTKUW1WT	PDE3A_HUMAN	Decreases Activity	[26]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[27]

References

• [1] ClinicalTrials.gov (NCT01313494) A Chronic Obstructive Pulmonary Disease (COPD) Trial Investigating Roflumilast on Safety and Effectiveness in China, Hong Kong and Singapore:
• [2] 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: 558).
• [3] Effects of nebulized salbutamol on respiratory mechanics in adult respiratory distress syndrome. Intensive Care Med. 1997 Jan;23(1):58-64.
• [4] Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial. Pediatr Pulmonol. 2019 Apr;54(4):372-377.
• [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: 6962).
• [6] ClinicalTrials.gov (NCT01664624) Roflumilast Plus Alogliptin Proof-of-Mechanism Study in Type2 Diabetes. U.S. National Institutes of Health.
• [7] Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol). CNS Drugs. 2002;16(1):1-8.
• [8] 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.
• [9] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [10] Effect of carboxylesterase 1 c.428G>A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Br J Clin Pharmacol. 2015 Nov;80(5):1131-8.
• [11] SULT 1A3 single-nucleotide polymorphism and the single dose pharmacokinetics of inhaled salbutamol enantiomers: are some athletes at risk of higher urine levels? Drug Test Anal. 2015 Feb;7(2):109-13.
• [12] beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure. J Clin Endocrinol Metab. 2005 Apr;90(4):2301-7. doi: 10.1210/jc.2004-1356. Epub 2005 Feb 1.
• [13] Modulation of steroidogenic gene expression and hormone production of H295R cells by pharmaceuticals and other environmentally active compounds. Toxicol Appl Pharmacol. 2007 Dec 1;225(2):142-53.
• [14] Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis. Toxicol Sci. 2023 Nov 28;196(2):200-217. doi: 10.1093/toxsci/kfad088.
• [15] Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers. Br J Clin Pharmacol. 1987 Nov;24(5):645-53. doi: 10.1111/j.1365-2125.1987.tb03224.x.
• [16] A prospective study of the effects of prolonged timolol therapy on alpha- and beta-adrenoceptor and angiotensin II receptor mediated responses in normal subjects. Br J Clin Pharmacol. 1997 Mar;43(3):301-8. doi: 10.1111/j.1365-2125.1997.00559.x.
• [17] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [18] [Role of salbutamol in inducing apoptosis of cultured human airway smooth muscle cells]. Zhonghua Jie He He Hu Xi Za Zhi. 2001 Apr;24(4):219-24.
• [19] Mechanisms by which S-albuterol induces human bronchial smooth muscle cell proliferation. Int Arch Allergy Immunol. 2008;146(4):321-33. doi: 10.1159/000121466. Epub 2008 Mar 21.
• [20] Levalbuterol inhibits human airway smooth muscle cell proliferation: therapeutic implications in the management of asthma. Int Arch Allergy Immunol. 2006;139(3):225-36. doi: 10.1159/000091168. Epub 2006 Jan 27.
• [21] Elevation of creatine kinase from skeletal muscle associated with inhaled albuterol. Ann Allergy Asthma Immunol. 1996 Dec;77(6):488-90. doi: 10.1016/S1081-1206(10)63356-X.
• [22] 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.
• [23] Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment. BMC Cardiovasc Disord. 2004 Sep 28;4(1):16. doi: 10.1186/1471-2261-4-16.
• [24] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [25] Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol. 2011 Apr;51(4):586-93.
• [26] Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors. J Pharmacol Exp Ther. 2005 Aug;314(2):846-54. doi: 10.1124/jpet.105.083519. Epub 2005 May 18.
• [27] Roflumilast protects from cisplatin-induced testicular toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line. Role of NF-B-p65, cAMP/PKA and Nrf2/HO-1, NQO1 signaling. Food Chem Toxicol. 2021 May;151:112133. doi: 10.1016/j.fct.2021.112133. Epub 2021 Mar 20.