Details of the Drug Combination

General Information of Drug Combination (ID: DCQ9UT1)

Drug Combination Name
Bosentan Alprostadil
Indication
Disease Entry Status REF
Raynaud's Phenomenon Phase 1 [1]
Component Drugs Bosentan   DMIOGBU Alprostadil   DMWH7NQ
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 Bosentan
Disease Entry ICD 11 Status REF
Pulmonary arterial hypertension BB01.0 Approved [2]
Pulmonary hypertension BB01 Approved [3]
Scleroderma 4A42 Investigative [3]
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 [8]
Endothelin B receptor (EDNRB) TT3ZTGU EDNRB_HUMAN Modulator [8]
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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 [9]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [9]
Organic anion transporting polypeptide 2B1 (SLCO2B1) DTPFTEQ SO2B1_HUMAN Substrate [9]
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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 [10]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [11]
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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 [12]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1) OTNEN8QK SO1B1_HUMAN Decreases Expression [7]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Expression [7]
Endothelin-1 (EDN1) OTZCACEG EDN1_HUMAN Decreases Activity [13]
Nitric oxide synthase 3 (NOS3) OTLDT7NR NOS3_HUMAN Increases ADR [14]
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Increases Expression [12]
Serine/threonine-protein kinase DCLK1 (DCLK1) OTVSPS98 DCLK1_HUMAN Affects Expression [7]
Kynurenine 3-monooxygenase (KMO) OT3MRMM9 KMO_HUMAN Affects Expression [7]
Carbonic anhydrase 12 (CA12) OT6WNFU8 CAH12_HUMAN Affects Expression [7]
All-trans-retinol dehydrogenase ADH1B (ADH1B) OTV3TB81 ADH1B_HUMAN Decreases Expression [7]
Alcohol dehydrogenase 1C (ADH1C) OTO1DV7F ADH1G_HUMAN Decreases Expression [7]
Superoxide dismutase (SOD1) OT39TA1L SODC_HUMAN Decreases Expression [7]
Complement component C9 (C9) OT7I5FDX CO9_HUMAN Affects Expression [7]
Catalase (CAT) OTHEBX9R CATA_HUMAN Decreases Expression [7]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [7]
Insulin-like growth factor I (IGF1) OTIIZR61 IGF1_HUMAN Affects Expression [7]
Fructose-bisphosphate aldolase B (ALDOB) OT7FR69A ALDOB_HUMAN Decreases Expression [7]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases Expression [7]
Fatty acid-binding protein, liver (FABP1) OTR34ETM FABPL_HUMAN Decreases Expression [7]
Glutathione peroxidase 1 (GPX1) OTE2O72Q GPX1_HUMAN Decreases Expression [7]
Alcohol dehydrogenase 1A (ADH1A) OTTS983E ADH1A_HUMAN Decreases Expression [7]
Amino acid transporter heavy chain SLC3A2 (SLC3A2) OTBR33M9 4F2_HUMAN Increases Expression [7]
All-trans-retinol dehydrogenase ADH4 (ADH4) OTKDKKNG ADH4_HUMAN Decreases Expression [7]
Heme oxygenase 1 (HMOX1) OTC1W6UX HMOX1_HUMAN Increases Expression [7]
Glutathione S-transferase theta-2 (GSTT2) OTANW3TJ GST2_HUMAN Decreases Expression [7]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases Expression [7]
Microsomal glutathione S-transferase 1 (MGST1) OTGN1KVZ MGST1_HUMAN Decreases Expression [7]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1) OTNAZVKB 3BHS1_HUMAN Affects Expression [7]
NAD(P)H dehydrogenase 1 (NQO1) OTZGGIVK NQO1_HUMAN Increases Expression [7]
NADPH--cytochrome P450 reductase (POR) OTVIDOCH NCPR_HUMAN Affects Expression [7]
Tyrosine aminotransferase (TAT) OT2CJ91O ATTY_HUMAN Affects Expression [7]
Phosphatidylcholine translocator ABCB4 (ABCB4) OTE6PY83 MDR3_HUMAN Decreases Expression [7]
Cytochrome P450 7A1 (CYP7A1) OT8Z5KLD CP7A1_HUMAN Decreases Expression [7]
Macrophage mannose receptor 1 (MRC1) OTTVCOPT MRC1_HUMAN Affects Expression [7]
Cytochrome P450 3A7 (CYP3A7) OTTCDHHM CP3A7_HUMAN Affects Expression [7]
Serum paraoxonase/arylesterase 1 (PON1) OTD0Z2XO PON1_HUMAN Decreases Expression [7]
G0/G1 switch protein 2 (G0S2) OT8FL49L G0S2_HUMAN Affects Expression [7]
Sodium- and chloride-dependent GABA transporter 1 (SLC6A1) OTLCJJF3 SC6A1_HUMAN Affects Expression [7]
Pyruvate kinase PKLR (PKLR) OTTTM1QI KPYR_HUMAN Affects Expression [7]
Carbamoyl-phosphate synthase , mitochondrial (CPS1) OTXV8NSR CPSM_HUMAN Decreases Expression [7]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1) OTJ6FM9F G6PC1_HUMAN Affects Expression [7]
Peroxisome proliferator-activated receptor gamma (PPARG) OTHMARHO PPARG_HUMAN Decreases Expression [7]
Hepatocyte nuclear factor 4-alpha (HNF4A) OTY1TOAB HNF4A_HUMAN Decreases Expression [7]
Glutamate--cysteine ligase catalytic subunit (GCLC) OTESDI4D GSH1_HUMAN Increases Expression [7]
Sulfotransferase 1E1 (SULT1E1) OTGPJ517 ST1E1_HUMAN Affects Expression [7]
Achaete-scute homolog 1 (ASCL1) OTI4X44G ASCL1_HUMAN Affects Expression [7]
Oxysterols receptor LXR-beta (NR1H2) OT4APA60 NR1H2_HUMAN Decreases Expression [7]
Microsomal triglyceride transfer protein large subunit (MTTP) OTNUVSDT MTP_HUMAN Decreases Expression [7]
Inhibin beta E chain (INHBE) OTOI2NYG INHBE_HUMAN Affects Expression [7]
Metallothionein-1X (MT1X) OT9AKFVS MT1X_HUMAN Increases Expression [7]
Complement factor H-related protein 3 (CFHR3) OTYL8SDO FHR3_HUMAN Affects Expression [7]
Oxysterols receptor LXR-alpha (NR1H3) OT54YZ9I NR1H3_HUMAN Decreases Expression [7]
Nuclear factor 1 X-type (NFIX) OT1DPZAE NFIX_HUMAN Decreases Expression [7]
Phosphoenolpyruvate carboxykinase , mitochondrial (PCK2) OTJ8LX4N PCKGM_HUMAN Decreases Expression [7]
Organic solute transporter subunit alpha (SLC51A) OTDJRZ0P OSTA_HUMAN Increases Expression [7]
Organic solute transporter subunit beta (SLC51B) OT4WYPSR OSTB_HUMAN Increases Expression [7]
Liver-expressed antimicrobial peptide 2 (LEAP2) OTUOPIS5 LEAP2_HUMAN Affects Expression [7]
N-acetylmuramoyl-L-alanine amidase (PGLYRP2) OTF8319A PGRP2_HUMAN Affects Expression [7]
Bile acid receptor (NR1H4) OTWZLPTB NR1H4_HUMAN Decreases Expression [7]
Normal mucosa of esophagus-specific gene 1 protein (C15ORF48) OT85J32K NMES1_HUMAN Affects Expression [7]
ATP-binding cassette sub-family G member 5 (ABCG5) OT1OMY93 ABCG5_HUMAN Affects Expression [7]
2-aminomuconic semialdehyde dehydrogenase (ALDH8A1) OTINY3MW AL8A1_HUMAN Affects Expression [7]
Cytochrome P450 3A43 (CYP3A43) OTMXADGA CP343_HUMAN Affects Expression [7]
NADPH oxidase 4 (NOX4) OTTYQ097 NOX4_HUMAN Decreases Expression [7]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) OTHCDQ22 PRGC1_HUMAN Decreases Expression [7]
Solute carrier family 22 member 7 (SLC22A7) OTKTNH1W S22A7_HUMAN Affects Expression [7]
ATP-binding cassette sub-family C member 3 (ABCC3) OTC3IJV4 MRP3_HUMAN Decreases Expression [15]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Decreases Expression [15]
Coxsackievirus and adenovirus receptor (CXADR) OT9ZP02A CXAR_HUMAN Decreases Expression [16]
Hepatic sodium/bile acid cotransporter (SLC10A1) OTUJVMCL NTCP_HUMAN Decreases Expression [15]
ATP-binding cassette sub-family C member 2 (ABCC2) OTJSIGV5 MRP2_HUMAN Decreases Expression [15]
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⏷ Show the Full List of 71 DOT(s)
Indication(s) of Alprostadil
Disease Entry ICD 11 Status REF
Aorta coarctation N.A. Approved [4]
Diabetic foot ulcer BD54 Approved [5]
Erectile dysfunction HA01.1 Approved [6]
Pulmonary hypertension BB01 Approved [4]
Tetralogy of fallot N.A. Approved [4]
Alprostadil Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Prostaglandin E2 receptor EP2 (PTGER2) TT1ZAVI PE2R2_HUMAN Agonist [5]
Thromboxane A2 receptor (TBXA2R) TT2O84V TA2R_HUMAN Modulator [18]
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Alprostadil Interacts with 4 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Multidrug resistance-associated protein 4 (ABCC4) DTCSGPB MRP4_HUMAN Substrate [19]
Organic anion transporter 1 (SLC22A6) DTQ23VB S22A6_HUMAN Substrate [20]
Organic anion transporting polypeptide 2A1 (SLCO2A1) DT021JD SO2A1_HUMAN Substrate [21]
Organic anion transporting polypeptide 3A1 (SLCO3A1) DTVNRXW SO3A1_HUMAN Substrate [22]
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Alprostadil Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Prostaglandin dehydrogenase 1 (HPGD) DEHKSC6 PGDH_HUMAN Metabolism [23]
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Alprostadil Interacts with 7 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Prostaglandin D2 receptor (PTGDR) OT92UR1A PD2R_HUMAN Affects Binding [24]
Renin (REN) OT52GZR2 RENI_HUMAN Increases Expression [25]
Angiotensinogen (AGT) OTBZLYR3 ANGT_HUMAN Increases Expression [25]
Natriuretic peptides A (NPPA) OTMQNTNX ANF_HUMAN Decreases Expression [26]
Beta-2 adrenergic receptor (ADRB2) OTSDOX4Q ADRB2_HUMAN Increases Phosphorylation [27]
Natriuretic peptides B (NPPB) OTSN2IPY ANFB_HUMAN Decreases Expression [28]
Vasopressin V1a receptor (AVPR1A) OTKR8AFL V1AR_HUMAN Increases ADR [14]
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⏷ Show the Full List of 7 DOT(s)

References

1 ClinicalTrials.gov (NCT01378845) Prognostic Influence of Light Rheography Measurement of Patients With Secondary Raynaud Syndrome With Ulcers on Hands
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: 3494).
3 Bosentan FDA Label
4 Alprostadil FDA Label
5 Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
6 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: 1882).
7 Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
8 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
9 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.
10 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.
11 Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301.
12 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.
13 ?-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.
14 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.
15 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.
16 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.
17 Arsenic trioxide-mediated antiplatelet activity: pivotal role of the phospholipase C gamma 2-protein kinase C-p38 MAPK cascade. Transl Res. 2010 Feb;155(2):97-108. doi: 10.1016/j.trsl.2009.08.005. Epub 2009 Sep 15.
18 Flow after prostaglandin E1 is mediated by receptor-coupled adenylyl cyclase in human anterior segments. Invest Ophthalmol Vis Sci. 1999 Oct;40(11):2622-6.
19 The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9.
20 Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3. Prostaglandins Other Lipid Mediat. 2016 Jan;122:10-7.
21 Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT). J Clin Invest. 1996 Sep 1;98(5):1142-9.
22 Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97.
23 Effect of calcium ionophore A23187 on prostaglandin synthase type 2 and 15-hydroxy-prostaglandin dehydrogenase expression in human chorion trophoblast cells. Am J Obstet Gynecol. 2008 Nov;199(5):554.e1-8.
24 Characterization of the recombinant human prostanoid DP receptor and identification of L-644,698, a novel selective DP agonist. Br J Pharmacol. 1998 Apr;123(7):1317-24.
25 Catecholamine and renin-angiotensin response during controlled hypotension induced by prostaglandin E1 combined with hemodilution during isoflurane anesthesia. J Clin Anesth. 1997 Jun;9(4):321-7. doi: 10.1016/s0952-8180(97)00011-1.
26 Effects of prostaglandin E1, dobutamine and placebo on hemodynamic, renal and neurohumoral variables in patients with advanced heart failure. Jpn Heart J. 1999 May;40(3):321-34. doi: 10.1536/jhj.40.321.
27 Characterization of agonist stimulation of cAMP-dependent protein kinase and G protein-coupled receptor kinase phosphorylation of the beta2-adrenergic receptor using phosphoserine-specific antibodies. Mol Pharmacol. 2004 Jan;65(1):196-206. doi: 10.1124/mol.65.1.196.
28 Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure. Eur J Heart Fail. 2005 Dec;7(7):1156-63. doi: 10.1016/j.ejheart.2005.05.001. Epub 2005 Aug 5.