Details of the Drug Combination

General Information of Drug Combination (ID: DCF950S)

• Drug Combination Name: Isoproterenol + Repaglinide
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Isoproterenol (DMK7MEY): Small molecular drug
  Repaglinide (DM5SXUV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 22.14
  Bliss Independence Score: 22.14
  Loewe Additivity Score: 33.54
  LHighest Single Agent (HSA) Score: 33.54

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Isoproterenol

Disease Entry	ICD 11	Status	REF
Atrioventricular block	N.A.	Approved	[2]
Cardiac arrest	MC82	Approved	[2]
Common cold	CA00	Approved	[2]
Heart block	BC63	Approved	[3]
Melanoma	2C30	Phase 1	[4]

Isoproterenol Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[7]
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Modulator	[7]
Interleukin-12 beta (IL12B)	TTGW72V	IL12B_HUMAN	Modulator	[8]

Isoproterenol Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[9]

Isoproterenol Interacts with 40 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptotic protease-activating factor 1 (APAF1)	OTJWIVY0	APAF_HUMAN	Increases Expression	[6]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[6]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[6]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[6]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[6]
Heat shock cognate 71 kDa protein (HSPA8)	OTJI2RCI	HSP7C_HUMAN	Decreases Expression	[6]
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)	OT2D9DOV	TNR1A_HUMAN	Decreases Expression	[6]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[6]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[6]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Decreases Expression	[6]
Metalloproteinase inhibitor 3 (TIMP3)	OTDGQAD1	TIMP3_HUMAN	Increases Expression	[6]
Heat shock-related 70 kDa protein 2 (HSPA2)	OTSDET7B	HSP72_HUMAN	Increases Expression	[6]
C-C motif chemokine 7 (CCL7)	OTDIS99H	CCL7_HUMAN	Decreases Expression	[6]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[6]
Four and a half LIM domains protein 1 (FHL1)	OTN535SU	FHL1_HUMAN	Decreases Expression	[6]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[6]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Decreases Expression	[6]
Regenerating islet-derived protein 3-gamma (REG3G)	OTLIUY8Z	REG3G_HUMAN	Decreases Expression	[6]
Metalloproteinase inhibitor 4 (TIMP4)	OT8A68SW	TIMP4_HUMAN	Decreases Expression	[6]
Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2)	OTAQD3YV	ARNT2_HUMAN	Decreases Expression	[6]
Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN)	OT5LIL3W	HIF1N_HUMAN	Decreases Expression	[6]
Hypoxia-inducible factor 3-alpha (HIF3A)	OTPWAAMC	HIF3A_HUMAN	Increases Expression	[6]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[11]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[12]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases Expression	[13]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[10]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases Expression	[14]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Expression	[16]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Beta-3 adrenergic receptor (ADRB3)	OTPMG4V7	ADRB3_HUMAN	Increases Activity	[17]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[13]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[18]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[10]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Phosphorylation	[19]
Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL)	OTESDTEU	GNAL_HUMAN	Increases Response To Substance	[20]
Neuroendocrine secretory protein 55 (GNAS)	OTMH8BKJ	GNAS3_HUMAN	Increases Response To Substance	[20]
Interleukin-5 receptor subunit alpha (IL5RA)	OTMSLUG9	IL5RA_HUMAN	Affects Response To Substance	[21]

Indication(s) of Repaglinide

Disease Entry	ICD 11	Status	REF
Diabetic complication	5A2Y	Approved	[5]

Repaglinide Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette transporter C9 (ABCC9)	TTEF5MJ	ABCC9_HUMAN	Blocker	[22]
ATP-binding cassette transporter C8 (ABCC8)	TTP835K	ABCC8_HUMAN	Blocker	[22]

Repaglinide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[23]

Repaglinide Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[24]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[25]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[24]

Repaglinide Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Affects Metabolism	[26]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[27]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[28]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Affects Expression	[29]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[29]

References

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• [2] Isoproterenol FDA Label
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• [18] A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. doi: 10.1073/pnas.0707936104. Epub 2007 Oct 9.
• [19] Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med. 2011 Jul 10;17(8):1003-9. doi: 10.1038/nm.2406.
• [20] Identification of specific ligands for orphan olfactory receptors. G protein-dependent agonism and antagonism of odorants. J Biol Chem. 2005 Mar 25;280(12):11807-15. doi: 10.1074/jbc.M411508200. Epub 2004 Dec 14.
• [21] Autocrine interaction between IL-5 and IL-1beta mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest. 1999 Sep;104(5):657-67. doi: 10.1172/JCI7137.
• [22] Metformin/Repaglinide (PrandiMet) for type 2 diabetes. Med Lett Drugs Ther. 2009 Jun 1;51(1313):41-3.
• [23] Disease-Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium. Clin Pharmacol Ther. 2018 Nov;104(5):900-915.
• [24] Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. Clin Pharmacokinet. 2007;46(2):93-108.
• [25] Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism. Br J Clin Pharmacol. 2010 Dec;70(6):870-80.
• [26] Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther. 2005 Jun;77(6):468-78. doi: 10.1016/j.clpt.2005.01.018.
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