General Information of Drug Combination (ID: DCZ1DCR)

Drug Combination Name
Sildenafil Bosentan
Indication
Disease Entry Status REF
Persistent Pulmonary Hypertension of the Newborn Phase 1 [1]
Component Drugs Sildenafil   DM4YDAJ Bosentan   DMIOGBU
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
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]
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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]
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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]
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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]
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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]
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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]
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⏷ Show the Full List of 71 DOT(s)

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]
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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