Details of the Drug Combination

General Information of Drug Combination (ID: DCCJ69R)

• Drug Combination Name: Enalaprilat + Aprepitant
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Enalaprilat (DMFYAM1): N.A.
  Aprepitant (DM053KT): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 13.46
  Bliss Independence Score: 13.46
  Loewe Additivity Score: 22.8
  LHighest Single Agent (HSA) Score: 22.8

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Enalaprilat

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]

Enalaprilat Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[8]

Enalaprilat Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[9]

Enalaprilat Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Dipeptidase (pepV)	DEQMBHW	Q84BU9_LACLH	Metabolism	[10]

Enalaprilat Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Secretion	[11]
B1 bradykinin receptor (BDKRB1)	OT1DHSVQ	BKRB1_HUMAN	Increases Activity	[12]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Uptake	[13]
Solute carrier family 22 member 11 (SLC22A11)	OTAJLNJZ	S22AB_HUMAN	Increases Uptake	[13]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Affects Abundance	[14]

Indication(s) of Aprepitant

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[4]
Nausea	MD90	Approved	[5]
Vomiting	MD90	Approved	[6]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[7]

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	[15]

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	[16]

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	[17]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[18]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[18]

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	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[19]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[19]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[19]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[19]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[19]

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] Enalaprilat FDA Label
• [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: 6332).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] 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).
• [6] Aprepitant FDA Label
• [7] 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.
• [8] Analysis of Vancomycin in the Hindlimb Vascular Bed of the Rat. Am J Ther. 1996 Oct;3(10):681-687.
• [9] Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74.
• [10] Characterization and kinetic analysis of enzyme-substrate recognition by three recombinant lactococcal PepVs. Arch Biochem Biophys. 2006 Oct 15;454(2):137-45.
• [11] Different effects of angiotensin converting enzyme inhibitors on endothelin-1 and nitric oxide balance in human vascular endothelial cells: evidence of an oxidant-sensitive pathway. Mediators Inflamm. 2008;2008:305087. doi: 10.1155/2008/305087. Epub 2008 Dec 1.
• [12] Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem. 2002 May 10;277(19):16847-52. doi: 10.1074/jbc.M200355200. Epub 2002 Mar 5.
• [13] Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule. Pharmaceutics. 2020 Sep 30;12(10):935. doi: 10.3390/pharmaceutics12100935.
• [14] Effect of organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphism on the single- and multiple-dose pharmacokinetics of enalapril in healthy Chinese adult men. Clin Ther. 2011 May;33(5):655-63. doi: 10.1016/j.clinthera.2011.04.018.
• [15] Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists. J Med Chem. 2009 May 14;52(9):3039-46.
• [16] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [17] Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol. 2005 Jun;55(6):609-16.
• [18] 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.
• [19] 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.