Details of the Drug Combination

General Information of Drug Combination (ID: DC9BLWY)

• Drug Combination Name: Aprepitant + Aminosalicylic Acid
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Aprepitant (DM053KT): Small molecular drug
  Aminosalicylic Acid (DMENSL5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 42.66
  Bliss Independence Score: 42.66
  Loewe Additivity Score: 52.69
  LHighest Single Agent (HSA) Score: 52.69

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	[7]

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	[8]

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	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]

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	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[11]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[11]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[11]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[11]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[11]

Indication(s) of Aminosalicylic Acid

Disease Entry	ICD 11	Status	REF
Crohn disease	DD70	Approved	[6]
Inflammatory bowel disease	DD72	Approved	[2]
Pulmonary and extrapulmonary tuberculosis	1B10.Z	Approved	[2]
Pulmonary tuberculosis	1B10.Z	Approved	[6]
Ulcerative colitis	DD71	Approved	[6]

Aminosalicylic Acid Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dihydrofolate reductase (DHFR)	TTYZVDJ	DYR_HUMAN	Modulator	[12]
Prostaglandin G/H synthase 1 (COX-1)	TT8NGED	PGH1_HUMAN	Modulator	[12]
Prostaglandin G/H synthase 2 (COX-2)	TTVKILB	PGH2_HUMAN	Modulator	[12]

Aminosalicylic Acid Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Sodium-coupled neutral amino acid transporter 3 (SLC38A3)	DTKWJH3	S38A3_HUMAN	Substrate	[13]

Aminosalicylic Acid Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
N-acetyltransferase 2 (NAT2)	DER7TA0	ARY2_HUMAN	Metabolism	[14]

Aminosalicylic Acid Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[15]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[15]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[15]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[15]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[15]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[15]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[15]
Arylamine N-acetyltransferase 1 (NAT1)	OTCCNQ3H	ARY1_HUMAN	Increases Acetylation	[16]

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] Aminosalicylic acid FDA Label
• [7] Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists. J Med Chem. 2009 May 14;52(9):3039-46.
• [8] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [9] Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol. 2005 Jun;55(6):609-16.
• [10] 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.
• [11] 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.
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [13] Identification of amino acids imparting acceptor substrate selectivity to human arylamine acetyltransferases NAT1 and NAT2. Biochem J. 2000 May 15;348 Pt 1:159-66.
• [14] Importance of the evaluation of N-acetyltransferase enzyme activity prior to 5-aminosalicylic acid medication for ulcerative colitis. Inflamm Bowel Dis. 2016 Aug;22(8):1793-802.
• [15] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [16] Eukaryotic arylamine N-acetyltransferase. Investigation of substrate specificity by high-throughput screening. Biochem Pharmacol. 2005 Jan 15;69(2):347-59. doi: 10.1016/j.bcp.2004.09.014. Epub 2004 Nov 24.