General Information of Drug Combination (ID: DCYQQJH)

Drug Combination Name
Mephenytoin Bosentan
Indication
Disease Entry Status REF
Chronic myelogenous leukemia Investigative [1]
Component Drugs Mephenytoin   DM5UGDK Bosentan   DMIOGBU
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: KBM-7
Zero Interaction Potency (ZIP) Score: 1.14
Bliss Independence Score: 1.14
Loewe Additivity Score: 16.31
LHighest Single Agent (HSA) Score: 16.31

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Mephenytoin
Disease Entry ICD 11 Status REF
Epilepsy 8A60-8A68 Approved [2]
Mephenytoin Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Voltage-gated sodium channel alpha Nav1.5 (SCN5A) TTZOVE0 SCN5A_HUMAN Blocker [5]
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Mephenytoin Interacts with 9 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [6]
Cytochrome P450 1A2 (CYP1A2) DEJGDUW CP1A2_HUMAN Metabolism [7]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [8]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [6]
Cytochrome P450 2C18 (CYP2C18) DEZMWRE CP2CI_HUMAN Metabolism [9]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [10]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [9]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [11]
Mephenytoin 4-hydroxylase (CYP2C19) DEGTFWK CP2CJ_HUMAN Metabolism [12]
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⏷ Show the Full List of 9 DME(s)
Mephenytoin Interacts with 1 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Decreases Methylation [13]
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Indication(s) of Bosentan
Disease Entry ICD 11 Status REF
Pulmonary arterial hypertension BB01.0 Approved [3]
Pulmonary hypertension BB01 Approved [4]
Scleroderma 4A42 Investigative [4]
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 [15]
Endothelin B receptor (EDNRB) TT3ZTGU EDNRB_HUMAN Modulator [15]
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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 [16]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [16]
Organic anion transporting polypeptide 2B1 (SLCO2B1) DTPFTEQ SO2B1_HUMAN Substrate [16]
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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 [17]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [18]
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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 [19]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1) OTNEN8QK SO1B1_HUMAN Decreases Expression [14]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Expression [14]
Endothelin-1 (EDN1) OTZCACEG EDN1_HUMAN Decreases Activity [20]
Nitric oxide synthase 3 (NOS3) OTLDT7NR NOS3_HUMAN Increases ADR [21]
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Increases Expression [19]
Serine/threonine-protein kinase DCLK1 (DCLK1) OTVSPS98 DCLK1_HUMAN Affects Expression [14]
Kynurenine 3-monooxygenase (KMO) OT3MRMM9 KMO_HUMAN Affects Expression [14]
Carbonic anhydrase 12 (CA12) OT6WNFU8 CAH12_HUMAN Affects Expression [14]
All-trans-retinol dehydrogenase ADH1B (ADH1B) OTV3TB81 ADH1B_HUMAN Decreases Expression [14]
Alcohol dehydrogenase 1C (ADH1C) OTO1DV7F ADH1G_HUMAN Decreases Expression [14]
Superoxide dismutase (SOD1) OT39TA1L SODC_HUMAN Decreases Expression [14]
Complement component C9 (C9) OT7I5FDX CO9_HUMAN Affects Expression [14]
Catalase (CAT) OTHEBX9R CATA_HUMAN Decreases Expression [14]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [14]
Insulin-like growth factor I (IGF1) OTIIZR61 IGF1_HUMAN Affects Expression [14]
Fructose-bisphosphate aldolase B (ALDOB) OT7FR69A ALDOB_HUMAN Decreases Expression [14]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases Expression [14]
Fatty acid-binding protein, liver (FABP1) OTR34ETM FABPL_HUMAN Decreases Expression [14]
Glutathione peroxidase 1 (GPX1) OTE2O72Q GPX1_HUMAN Decreases Expression [14]
Alcohol dehydrogenase 1A (ADH1A) OTTS983E ADH1A_HUMAN Decreases Expression [14]
Amino acid transporter heavy chain SLC3A2 (SLC3A2) OTBR33M9 4F2_HUMAN Increases Expression [14]
All-trans-retinol dehydrogenase ADH4 (ADH4) OTKDKKNG ADH4_HUMAN Decreases Expression [14]
Heme oxygenase 1 (HMOX1) OTC1W6UX HMOX1_HUMAN Increases Expression [14]
Glutathione S-transferase theta-2 (GSTT2) OTANW3TJ GST2_HUMAN Decreases Expression [14]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases Expression [14]
Microsomal glutathione S-transferase 1 (MGST1) OTGN1KVZ MGST1_HUMAN Decreases Expression [14]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1) OTNAZVKB 3BHS1_HUMAN Affects Expression [14]
NAD(P)H dehydrogenase 1 (NQO1) OTZGGIVK NQO1_HUMAN Increases Expression [14]
NADPH--cytochrome P450 reductase (POR) OTVIDOCH NCPR_HUMAN Affects Expression [14]
Tyrosine aminotransferase (TAT) OT2CJ91O ATTY_HUMAN Affects Expression [14]
Phosphatidylcholine translocator ABCB4 (ABCB4) OTE6PY83 MDR3_HUMAN Decreases Expression [14]
Cytochrome P450 7A1 (CYP7A1) OT8Z5KLD CP7A1_HUMAN Decreases Expression [14]
Macrophage mannose receptor 1 (MRC1) OTTVCOPT MRC1_HUMAN Affects Expression [14]
Cytochrome P450 3A7 (CYP3A7) OTTCDHHM CP3A7_HUMAN Affects Expression [14]
Serum paraoxonase/arylesterase 1 (PON1) OTD0Z2XO PON1_HUMAN Decreases Expression [14]
G0/G1 switch protein 2 (G0S2) OT8FL49L G0S2_HUMAN Affects Expression [14]
Sodium- and chloride-dependent GABA transporter 1 (SLC6A1) OTLCJJF3 SC6A1_HUMAN Affects Expression [14]
Pyruvate kinase PKLR (PKLR) OTTTM1QI KPYR_HUMAN Affects Expression [14]
Carbamoyl-phosphate synthase , mitochondrial (CPS1) OTXV8NSR CPSM_HUMAN Decreases Expression [14]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1) OTJ6FM9F G6PC1_HUMAN Affects Expression [14]
Peroxisome proliferator-activated receptor gamma (PPARG) OTHMARHO PPARG_HUMAN Decreases Expression [14]
Hepatocyte nuclear factor 4-alpha (HNF4A) OTY1TOAB HNF4A_HUMAN Decreases Expression [14]
Glutamate--cysteine ligase catalytic subunit (GCLC) OTESDI4D GSH1_HUMAN Increases Expression [14]
Sulfotransferase 1E1 (SULT1E1) OTGPJ517 ST1E1_HUMAN Affects Expression [14]
Achaete-scute homolog 1 (ASCL1) OTI4X44G ASCL1_HUMAN Affects Expression [14]
Oxysterols receptor LXR-beta (NR1H2) OT4APA60 NR1H2_HUMAN Decreases Expression [14]
Microsomal triglyceride transfer protein large subunit (MTTP) OTNUVSDT MTP_HUMAN Decreases Expression [14]
Inhibin beta E chain (INHBE) OTOI2NYG INHBE_HUMAN Affects Expression [14]
Metallothionein-1X (MT1X) OT9AKFVS MT1X_HUMAN Increases Expression [14]
Complement factor H-related protein 3 (CFHR3) OTYL8SDO FHR3_HUMAN Affects Expression [14]
Oxysterols receptor LXR-alpha (NR1H3) OT54YZ9I NR1H3_HUMAN Decreases Expression [14]
Nuclear factor 1 X-type (NFIX) OT1DPZAE NFIX_HUMAN Decreases Expression [14]
Phosphoenolpyruvate carboxykinase , mitochondrial (PCK2) OTJ8LX4N PCKGM_HUMAN Decreases Expression [14]
Organic solute transporter subunit alpha (SLC51A) OTDJRZ0P OSTA_HUMAN Increases Expression [14]
Organic solute transporter subunit beta (SLC51B) OT4WYPSR OSTB_HUMAN Increases Expression [14]
Liver-expressed antimicrobial peptide 2 (LEAP2) OTUOPIS5 LEAP2_HUMAN Affects Expression [14]
N-acetylmuramoyl-L-alanine amidase (PGLYRP2) OTF8319A PGRP2_HUMAN Affects Expression [14]
Bile acid receptor (NR1H4) OTWZLPTB NR1H4_HUMAN Decreases Expression [14]
Normal mucosa of esophagus-specific gene 1 protein (C15ORF48) OT85J32K NMES1_HUMAN Affects Expression [14]
ATP-binding cassette sub-family G member 5 (ABCG5) OT1OMY93 ABCG5_HUMAN Affects Expression [14]
2-aminomuconic semialdehyde dehydrogenase (ALDH8A1) OTINY3MW AL8A1_HUMAN Affects Expression [14]
Cytochrome P450 3A43 (CYP3A43) OTMXADGA CP343_HUMAN Affects Expression [14]
NADPH oxidase 4 (NOX4) OTTYQ097 NOX4_HUMAN Decreases Expression [14]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) OTHCDQ22 PRGC1_HUMAN Decreases Expression [14]
Solute carrier family 22 member 7 (SLC22A7) OTKTNH1W S22A7_HUMAN Affects Expression [14]
ATP-binding cassette sub-family C member 3 (ABCC3) OTC3IJV4 MRP3_HUMAN Decreases Expression [22]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Decreases Expression [22]
Coxsackievirus and adenovirus receptor (CXADR) OT9ZP02A CXAR_HUMAN Decreases Expression [23]
Hepatic sodium/bile acid cotransporter (SLC10A1) OTUJVMCL NTCP_HUMAN Decreases Expression [22]
ATP-binding cassette sub-family C member 2 (ABCC2) OTJSIGV5 MRP2_HUMAN Decreases Expression [22]
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⏷ Show the Full List of 71 DOT(s)

References

1 Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
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: 7223).
3 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).
4 Bosentan FDA Label
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10 Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans. Biochemistry. 1994 Feb 22;33(7):1743-52.
11 Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
12 Cytochromes P450 mediating the N-demethylation of amitriptyline. Br J Clin Pharmacol. 1997 Feb;43(2):137-44.
13 Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos. 2002 Dec;30(12):1311-9.
14 Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
15 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
16 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.
17 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.
18 Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301.
19 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.
20 ?-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.
21 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.
22 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.
23 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.