Details of the Drug Combination

General Information of Drug Combination (ID: DC7D3AQ)

• Drug Combination Name: Bepridil + Nizatidine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Bepridil (DM0RKS4): Small molecular drug
  Nizatidine (DMGFV3Z): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 30.24
  Bliss Independence Score: 30.24
  Loewe Additivity Score: 43.18
  LHighest Single Agent (HSA) Score: 43.2

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bepridil

Disease Entry	ICD 11	Status	REF
Chronic/stable angina	BA40.1	Approved	[2]

Bepridil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcium channel unspecific (CaC)	TT5HONZ	NOUNIPROTAC	Modulator	[5]

Bepridil Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Bepridil Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]

Bepridil Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[9]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[9]
Potassium voltage-gated channel subfamily A member 5 (KCNA5)	OTHI2N71	KCNA5_HUMAN	Decreases Activity	[10]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[9]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[9]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[11]
Eukaryotic translation initiation factor 2A (EIF2A)	OTWXELQP	EIF2A_HUMAN	Increases Phosphorylation	[9]

Indication(s) of Nizatidine

Disease Entry	ICD 11	Status	REF
Acid-reflux disorder	DA22	Approved	[3]
Gastric ulcer	DA60	Approved	[4]
Peptic esophagitis	N.A.	Approved	[4]
Peptic ulcer	DA61	Approved	[4]

Nizatidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H2 receptor (H2R)	TTQHJ1K	HRH2_HUMAN	Antagonist	[12]

Nizatidine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[14]

Nizatidine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Calcitonin (CALCA)	OTZ11LHB	CALC_HUMAN	Increases Expression	[15]
Protachykinin-1 (TAC1)	OTM842YW	TKN1_HUMAN	Increases Expression	[15]

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: 2337).
• [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: 7248).
• [4] Nizatidine FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] 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.
• [7] Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17.
• [8] Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity. Drug Metab Pharmacokinet. 2015 Aug;30(4):257-62.
• [9] Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-induced apoptosis via CHOP-mediated DR5 upregulation. Neuro Oncol. 2011 Mar;13(3):267-79. doi: 10.1093/neuonc/noq195. Epub 2011 Feb 3.
• [10] Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031. Eur J Pharmacol. 2001 Nov 2;430(2-3):149-57. doi: 10.1016/s0014-2999(01)01381-4.
• [11] Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds. Assay Drug Dev Technol. 2004 Oct;2(5):497-506. doi: 10.1089/adt.2004.2.497.
• [12] Does the use of nizatidine, as a pro-kinetic agent, improve gastric emptying in patients post-oesophagectomy J Gastrointest Surg. 2009 Mar;13(3):432-7.
• [13] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB00585)
• [14] 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.
• [15] Effects of histamine H(2)-receptor antagonists on human plasma levels of calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. J Pharm Pharmacol. 2002 Nov;54(11):1559-63. doi: 10.1211/002235702117.