Details of the Drug Combination

General Information of Drug Combination (ID: DC3ZQN2)

• Drug Combination Name: Aprepitant + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Aprepitant (DM053KT): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 7.54
  Bliss Independence Score: 7.54
  Loewe Additivity Score: 0.66
  LHighest Single Agent (HSA) Score: 0.66

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Aprepitant

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[2]
Nausea	MD90	Approved	[3]
Vomiting	MD90	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[5]

Aprepitant Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Substance-P receptor (TACR1)	TTZPO1L	NK1R_HUMAN	Antagonist	[8]

Aprepitant Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Aprepitant Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Aprepitant Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Phosphorylation	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[12]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[12]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[12]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[12]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[12]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[6]
Acute myeloid leukaemia	2A60	Approved	[7]
Adult acute monocytic leukemia	N.A.	Approved	[6]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[6]
Leukemia	N.A.	Approved	[6]

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	[14]

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	[15]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[16]

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	[17]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[17]

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	[13]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[18]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[13]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[19]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[20]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[13]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[21]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[13]

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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 3490).
• [4] Aprepitant FDA Label
• [5] ClinicalTrials.gov (NCT00571168) Efficacy and Safety of Aprepitant in Subjects With Multiple Myeloma During and After High-dose Chemotherapy. U.S. National Institutes of Health.
• [6] Idarubicin FDA Label
• [7] 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).
• [8] Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists. J Med Chem. 2009 May 14;52(9):3039-46.
• [9] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [10] Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol. 2005 Jun;55(6):609-16.
• [11] Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos. 2004 Nov;32(11):1287-92.
• [12] Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-B axis: Shedding new light on resistance to Aprepitant. Int J Biochem Cell Biol. 2018 Oct;103:105-114. doi: 10.1016/j.biocel.2018.08.010. Epub 2018 Aug 23.
• [13] 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.
• [14] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [15] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [16] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [17] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [18] 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.
• [19] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [20] 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.
• [21] 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.