Details of the Drug Combination

General Information of Drug Combination (ID: DCBZOVQ)

• Drug Combination Name: Rebamipide + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Rebamipide (DM2GHCR): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 14.71
  Bliss Independence Score: 14.71
  Loewe Additivity Score: 6.08
  LHighest Single Agent (HSA) Score: 6.08

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Rebamipide

Disease Entry	ICD 11	Status	REF
Peptic ulcer	DA61	Phase 3	[2]

Rebamipide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
N-formyl peptide receptor (FPR1)	TT5Y4EM	FPR1_HUMAN	Antagonist	[6]

Rebamipide Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Rebamipide Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[8]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Decreases Expression	[5]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Increases Expression	[5]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[5]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[5]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Increases Expression	[5]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Decreases Expression	[5]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[5]
Aurora kinase B (AURKB)	OTIY4VHU	AURKB_HUMAN	Decreases Expression	[8]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[10]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[3]
Acute myeloid leukaemia	2A60	Approved	[4]
Adult acute monocytic leukemia	N.A.	Approved	[3]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[3]
Leukemia	N.A.	Approved	[3]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[12]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[13]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]

Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[11]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[16]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[11]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[17]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[18]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[11]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[19]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[11]

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: 871).
• [3] Idarubicin FDA Label
• [4] 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: 7083).
• [5] Rebamipide suppresses 5-fluorouracil-induced cell death via the activation of Akt/mTOR pathway and regulates the expression of Bcl-2 family proteins. Toxicol In Vitro. 2018 Feb;46:284-293. doi: 10.1016/j.tiv.2017.10.019. Epub 2017 Oct 17.
• [6] Rebamipide suppresses formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production by inhibiting fMLP-receptor binding in human neutrophils. J Pharmacol Exp Ther. 2001 Apr;297(1):388-94.
• [7] Involvement of cytochrome P450 in the metabolism of rebamipide by the human liver. Xenobiotica. 2002 Jul;32(7):573-86.
• [8] Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. Biochem Biophys Res Commun. 2005 Aug 19;334(1):207-12. doi: 10.1016/j.bbrc.2005.05.204.
• [9] Management of recurrence of symptoms of gastroesophageal reflux disease: synergistic effect of rebamipide with 15 mg lansoprazole. Dig Dis Sci. 2010 Dec;55(12):3393-8. doi: 10.1007/s10620-010-1166-9. Epub 2010 Mar 3.
• [10] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.
• [11] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [13] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [14] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [15] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [16] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
• [17] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [18] The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
• [19] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.