Details of the Drug Combination

General Information of Drug Combination (ID: DCZ1DCR)

• Drug Combination Name: Sildenafil + Bosentan
• Indication: Persistent Pulmonary Hypertension of the Newborn; Status: Phase 1 [1]
• Component Drugs:
  Sildenafil (DM4YDAJ): Small molecular drug
  Bosentan (DMIOGBU): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sildenafil

Disease Entry	ICD 11	Status	REF
Alveolar capillary dysplasia with misalignment of pulmonary veins	N.A.	Approved	[2]
Erectile dysfunction	HA01.1	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Respiratory failure	CB41	Investigative	[2]

Sildenafil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN phosphodiesterase type 5 (PDE5)	TTRYFSB	PDE5A_HUMAN	Inhibitor	[7]

Sildenafil Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3)	OTA6HYBA	GBB3_HUMAN	Increases Response	[8]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Increases Response	[9]

Indication(s) of Bosentan

Disease Entry	ICD 11	Status	REF
Pulmonary arterial hypertension	BB01.0	Approved	[5]
Pulmonary hypertension	BB01	Approved	[6]
Scleroderma	4A42	Investigative	[6]

Bosentan Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Endothelin A receptor (EDNRA)	TTKRD0G	EDNRA_HUMAN	Modulator	[11]
Endothelin B receptor (EDNRB)	TT3ZTGU	EDNRB_HUMAN	Modulator	[11]

Bosentan Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[12]

Bosentan Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]

Bosentan Interacts with 71 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[15]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Expression	[10]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Expression	[10]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Activity	[16]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases ADR	[17]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[15]
Serine/threonine-protein kinase DCLK1 (DCLK1)	OTVSPS98	DCLK1_HUMAN	Affects Expression	[10]
Kynurenine 3-monooxygenase (KMO)	OT3MRMM9	KMO_HUMAN	Affects Expression	[10]
Carbonic anhydrase 12 (CA12)	OT6WNFU8	CAH12_HUMAN	Affects Expression	[10]
All-trans-retinol dehydrogenase ADH1B (ADH1B)	OTV3TB81	ADH1B_HUMAN	Decreases Expression	[10]
Alcohol dehydrogenase 1C (ADH1C)	OTO1DV7F	ADH1G_HUMAN	Decreases Expression	[10]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Decreases Expression	[10]
Complement component C9 (C9)	OT7I5FDX	CO9_HUMAN	Affects Expression	[10]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[10]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[10]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Affects Expression	[10]
Fructose-bisphosphate aldolase B (ALDOB)	OT7FR69A	ALDOB_HUMAN	Decreases Expression	[10]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[10]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Decreases Expression	[10]
Glutathione peroxidase 1 (GPX1)	OTE2O72Q	GPX1_HUMAN	Decreases Expression	[10]
Alcohol dehydrogenase 1A (ADH1A)	OTTS983E	ADH1A_HUMAN	Decreases Expression	[10]
Amino acid transporter heavy chain SLC3A2 (SLC3A2)	OTBR33M9	4F2_HUMAN	Increases Expression	[10]
All-trans-retinol dehydrogenase ADH4 (ADH4)	OTKDKKNG	ADH4_HUMAN	Decreases Expression	[10]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[10]
Glutathione S-transferase theta-2 (GSTT2)	OTANW3TJ	GST2_HUMAN	Decreases Expression	[10]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Microsomal glutathione S-transferase 1 (MGST1)	OTGN1KVZ	MGST1_HUMAN	Decreases Expression	[10]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1)	OTNAZVKB	3BHS1_HUMAN	Affects Expression	[10]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[10]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Affects Expression	[10]
Tyrosine aminotransferase (TAT)	OT2CJ91O	ATTY_HUMAN	Affects Expression	[10]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[10]
Cytochrome P450 7A1 (CYP7A1)	OT8Z5KLD	CP7A1_HUMAN	Decreases Expression	[10]
Macrophage mannose receptor 1 (MRC1)	OTTVCOPT	MRC1_HUMAN	Affects Expression	[10]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Affects Expression	[10]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Expression	[10]
G0/G1 switch protein 2 (G0S2)	OT8FL49L	G0S2_HUMAN	Affects Expression	[10]
Sodium- and chloride-dependent GABA transporter 1 (SLC6A1)	OTLCJJF3	SC6A1_HUMAN	Affects Expression	[10]
Pyruvate kinase PKLR (PKLR)	OTTTM1QI	KPYR_HUMAN	Affects Expression	[10]
Carbamoyl-phosphate synthase , mitochondrial (CPS1)	OTXV8NSR	CPSM_HUMAN	Decreases Expression	[10]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Affects Expression	[10]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[10]
Hepatocyte nuclear factor 4-alpha (HNF4A)	OTY1TOAB	HNF4A_HUMAN	Decreases Expression	[10]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[10]
Sulfotransferase 1E1 (SULT1E1)	OTGPJ517	ST1E1_HUMAN	Affects Expression	[10]
Achaete-scute homolog 1 (ASCL1)	OTI4X44G	ASCL1_HUMAN	Affects Expression	[10]
Oxysterols receptor LXR-beta (NR1H2)	OT4APA60	NR1H2_HUMAN	Decreases Expression	[10]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Decreases Expression	[10]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Affects Expression	[10]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Increases Expression	[10]
Complement factor H-related protein 3 (CFHR3)	OTYL8SDO	FHR3_HUMAN	Affects Expression	[10]
Oxysterols receptor LXR-alpha (NR1H3)	OT54YZ9I	NR1H3_HUMAN	Decreases Expression	[10]
Nuclear factor 1 X-type (NFIX)	OT1DPZAE	NFIX_HUMAN	Decreases Expression	[10]
Phosphoenolpyruvate carboxykinase , mitochondrial (PCK2)	OTJ8LX4N	PCKGM_HUMAN	Decreases Expression	[10]
Organic solute transporter subunit alpha (SLC51A)	OTDJRZ0P	OSTA_HUMAN	Increases Expression	[10]
Organic solute transporter subunit beta (SLC51B)	OT4WYPSR	OSTB_HUMAN	Increases Expression	[10]
Liver-expressed antimicrobial peptide 2 (LEAP2)	OTUOPIS5	LEAP2_HUMAN	Affects Expression	[10]
N-acetylmuramoyl-L-alanine amidase (PGLYRP2)	OTF8319A	PGRP2_HUMAN	Affects Expression	[10]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Expression	[10]
Normal mucosa of esophagus-specific gene 1 protein (C15ORF48)	OT85J32K	NMES1_HUMAN	Affects Expression	[10]
ATP-binding cassette sub-family G member 5 (ABCG5)	OT1OMY93	ABCG5_HUMAN	Affects Expression	[10]
2-aminomuconic semialdehyde dehydrogenase (ALDH8A1)	OTINY3MW	AL8A1_HUMAN	Affects Expression	[10]
Cytochrome P450 3A43 (CYP3A43)	OTMXADGA	CP343_HUMAN	Affects Expression	[10]
NADPH oxidase 4 (NOX4)	OTTYQ097	NOX4_HUMAN	Decreases Expression	[10]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Decreases Expression	[10]
Solute carrier family 22 member 7 (SLC22A7)	OTKTNH1W	S22A7_HUMAN	Affects Expression	[10]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[18]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[18]
Coxsackievirus and adenovirus receptor (CXADR)	OT9ZP02A	CXAR_HUMAN	Decreases Expression	[19]
Hepatic sodium/bile acid cotransporter (SLC10A1)	OTUJVMCL	NTCP_HUMAN	Decreases Expression	[18]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Pulmonary Hypertension	DCBTMZ7	N. A.	Phase 3	[20]
Pulmonary Arterial Hypertension	DCE3E40	N. A.	Phase 3	[21]
Pulmonary Arterial Hypertension	DC70BCK	N. A.	Phase 1	[22]

References

• [1] ClinicalTrials.gov (NCT04379180) Population Pharmacokinetics and Dosage Individualization of Oral Pulmonary Vasodilators in PPHN
• [2] Sildenafil FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 206401.
• [4] ClinicalTrials.gov (NCT04304313) A Pilot Study of Sildenafil in COVID-19. U.S. National Institutes of Health.
• [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: 3494).
• [6] Bosentan FDA Label
• [7] Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005 Feb;79(3):1966-9. doi: 10.1128/JVI.79.3.1966-1969.2005.
• [8] Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. J Urol. 2003 Mar;169(3):1048-51. doi: 10.1097/01.ju.0000058369.72348.ba.
• [9] ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction. Urology. 2003 Jul;62(1):152-7. doi: 10.1016/s0090-4295(03)00137-7.
• [10] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [11] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [12] Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos. 2007 Aug;35(8):1400-7.
• [13] Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos. 2007 Aug;35(8):1400-7.
• [14] Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301.
• [15] Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Drug Metab Dispos. 2008 Jun;36(6):1046-55.
• [16] ?-adrenoceptors and muscarinic receptors mediate opposing effects on endothelin-1 expression in human lung fibroblasts. Eur J Pharmacol. 2012 Sep 15;691(1-3):218-24. doi: 10.1016/j.ejphar.2012.07.002. Epub 2012 Jul 13.
• [17] 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.
• [18] From the Cover: MechanisticInsights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells. Toxicol Sci. 2017 Jun 1;157(2):451-464. doi: 10.1093/toxsci/kfx062.
• [19] Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells. J Gen Virol. 2010 Aug;91(Pt 8):1959-1970. doi: 10.1099/vir.0.020065-0. Epub 2010 Apr 14.
• [20] ClinicalTrials.gov (NCT00302211) The "VISION" Trial: Ventavis Inhalation With Sildenafil to Improve and Optimize Pulmonary Arterial Hypertension
• [21] ClinicalTrials.gov (NCT01392469) Pharmacokinetic Effects of QTI571 on Sildenafil and Bosentan in Pulmonary Arterial Hypertension Participants
• [22] ClinicalTrials.gov (NCT00433329) Combination Therapy in Pulmonary Arterial Hypertension