General Information of Drug Combination (ID: DCL0HWQ)

Drug Combination Name
Amiloride Itraconazole
Indication
Disease Entry Status REF
Chronic myelogenous leukemia Investigative [1]
Component Drugs Amiloride   DMRTSGP Itraconazole   DMCR1MV
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: 4.57
Bliss Independence Score: 4.57
Loewe Additivity Score: 19.62
LHighest Single Agent (HSA) Score: 19.62

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Amiloride
Disease Entry ICD 11 Status REF
Congestive heart failure BD10 Approved [2]
Edema MG29 Approved [3]
Amiloride Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Acid-sensing ion channel 1 (ASIC1) TTRJYB6 ASIC1_HUMAN Modulator [7]
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Amiloride Interacts with 2 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Organic cation transporter 2 (SLC22A2) DT9IDPW S22A2_HUMAN Substrate [8]
Organic cation transporter 1 (SLC22A1) DTT79CX S22A1_HUMAN Substrate [9]
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Amiloride Interacts with 15 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Diamine oxidase (AOC1) OTRC220K AOC1_HUMAN Decreases Activity [10]
3-phosphoinositide-dependent protein kinase 1 (PDPK1) OTT09ZVP PDPK1_HUMAN Decreases Phosphorylation [11]
Dysferlin (DYSF) OTNSKJU0 DYSF_HUMAN Decreases Expression [12]
Urokinase-type plasminogen activator (PLAU) OTX0QGKK UROK_HUMAN Decreases Activity [13]
Angiotensinogen (AGT) OTBZLYR3 ANGT_HUMAN Increases Expression [14]
Protein c-Fos (FOS) OTJBUVWS FOS_HUMAN Increases Expression [15]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Decreases Phosphorylation [11]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Decreases Activity [16]
Myogenic factor 5 (MYF5) OTTVO2S5 MYF5_HUMAN Increases Expression [12]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [17]
Pancreas/duodenum homeobox protein 1 (PDX1) OTX1DKRA PDX1_HUMAN Decreases Uptake [18]
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA) OT7Y43A1 PP1A_HUMAN Decreases Phosphorylation [11]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Decreases Activity [16]
Multidrug and toxin extrusion protein 1 (SLC47A1) OTZX0U5Q S47A1_HUMAN Decreases Activity [19]
Glutamate receptor-interacting protein 1 (GRIP1) OT958HK1 GRIP1_HUMAN Affects Response To Substance [20]
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⏷ Show the Full List of 15 DOT(s)
Indication(s) of Itraconazole
Disease Entry ICD 11 Status REF
Aspergillosis 1F20 Approved [4]
Blastomycosis 1F22 Approved [4]
Fungal infection 1F29-1F2F Approved [5]
Fusariosis N.A. Approved [4]
Histoplasmosis N.A. Approved [4]
Invasive candidiasis 1F23 Approved [4]
Mycoses 1F2Z Approved [4]
Candidemia 1F23.3Y Investigative [4]
Esophageal candidiasis N.A. Investigative [4]
Itraconazole Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Hedgehog signaling pathway (HS pathway) TT4LXBC NOUNIPROTAC Inhibitor [21]
Candida Cytochrome P450 51 (Candi ERG11) TTTSOUD CP51_CANAL Modulator [7]
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Itraconazole Interacts with 1 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [22]
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Itraconazole Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [23]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [24]
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Itraconazole Interacts with 10 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Decreases Expression [25]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Decreases Activity [26]
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1) OTG2T749 CP24A_HUMAN Decreases Activity [27]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Increases Expression [28]
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Increases Expression [29]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [30]
Interleukin-4 (IL4) OTOXBWAU IL4_HUMAN Decreases Expression [31]
Interleukin-5 (IL5) OTAFPSCO IL5_HUMAN Decreases Expression [31]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) OTHF4H9U DHI2_HUMAN Decreases Activity [32]
Lanosterol 14-alpha demethylase (CYP51A1) OTAYHG9C CP51A_HUMAN Decreases Response To Substance [33]
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⏷ Show the Full List of 10 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: 2421).
3 Amiloride FDA Label
4 Itraconazole FDA Label
5 FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076104.
6 Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leuk Res. 2007 Apr;31(4):507-14. doi: 10.1016/j.leukres.2006.06.015. Epub 2006 Aug 1.
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8 Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol. 2006 Jun;290(6):C1521-31.
9 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.
10 Diamine oxidase is the amiloride-binding protein and is inhibited by amiloride analogues. J Biol Chem. 1994 Apr 1;269(13):9921-5.
11 Role of HER-2/neu signaling in sensitivity to tumor necrosis factor-related apoptosis-inducing ligand: enhancement of TRAIL-mediated apoptosis by amiloride. J Cell Biochem. 2005 Oct 1;96(2):376-89. doi: 10.1002/jcb.20512.
12 In vivo and in vitro dysferlin expression in human muscle satellite cells. J Neuropathol Exp Neurol. 2004 Oct;63(10):1104-13. doi: 10.1093/jnen/63.10.1104.
13 Amplification of urokinase gene in prostate cancer. Cancer Res. 2001 Jul 15;61(14):5340-4.
14 Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
15 Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
16 Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
17 Reduction in the radiation-induced late S phase and G2 blocks in HL-60 cell populations by amiloride, an efficient inhibitor of the Na+/H+ transporter. Cancer Res. 1998 Feb 1;58(3):413-20.
18 PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant. 2005;14(9):637-45. doi: 10.3727/000000005783982648.
19 Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006 Nov;34(11):1868-74. doi: 10.1124/dmd.106.010876. Epub 2006 Aug 23.
20 Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.
21 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
22 Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
23 Effects of itraconazole and tandospirone on the pharmacokinetics of perospirone. Ther Drug Monit. 2006 Feb;28(1):73-5.
24 Investigation into UDP-glucuronosyltransferase (UGT) enzyme kinetics of imidazole- and triazole-containing antifungal drugs in human liver microsomes and recombinant UGT enzymes. Drug Metab Dispos. 2010 Jun;38(6):923-9.
25 Itraconazole cis-diastereoisomers activate aryl hydrocarbon receptor AhR and pregnane X receptor PXR and induce CYP1A1 in human cell lines and human hepatocytes. Toxicology. 2017 May 15;383:40-49.
26 Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. Ther Drug Monit. 2005 Jun;27(3):322-33. doi: 10.1097/01.ftd.0000150135.22645.ea.
27 The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
28 Induction of cytochrome P450 1A1 by ketoconazole and itraconazole but not fluconazole in murine and human hepatoma cell lines. Toxicol Sci. 2007 May;97(1):32-43.
29 Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression. Drug Metab Dispos. 2008 Feb;36(2):339-48.
30 Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
31 Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis. J Invest Dermatol. 2001 Dec;117(6):1635-46. doi: 10.1046/j.0022-202x.2001.01566.x.
32 Inhibition of 11-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Biochem Pharmacol. 2017 Apr 15;130:93-103. doi: 10.1016/j.bcp.2017.01.010. Epub 2017 Jan 25.
33 Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homolo... Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603.