Details of the Drug Combination

General Information of Drug Combination (ID: DCK40P4)

• Drug Combination Name: Loperamide + Everolimus
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Loperamide (DMOJZQ9): Small molecular drug
  Everolimus (DM8X2EH): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 7.72
  Bliss Independence Score: 7.72
  Loewe Additivity Score: 12.9
  LHighest Single Agent (HSA) Score: 12.92

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Loperamide

Disease Entry	ICD 11	Status	REF
Diarrhea	ME05.1	Approved	[2]
Traveler's diarrhea	ME05.1	Approved	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[4]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[4]

Loperamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor delta (OPRD1)	TT27RFC	OPRD_HUMAN	Binder	[8]

Loperamide 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]

Loperamide Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[11]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[11]
Oxygen-insensitive NADPH nitroreductase A (nfsA)	DEDPI65	NFSA_ECOLI	Metabolism	[12]

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[5]
Advanced/metastatic breast cancer	2C60	Approved	[2]
Brainstem neoplasm	N.A.	Approved	[5]
Breast carcinoma	N.A.	Approved	[5]
Graft-versus-host disease	4B24	Approved	[5]
Intracranial meningioma	N.A.	Approved	[5]
Leukemia	N.A.	Approved	[5]
Lung cancer	2C25.0	Approved	[5]
Mucosal melanoma	N.A.	Approved	[5]
Multiple sclerosis	8A40	Approved	[5]
Plasma cell myeloma	2A83.1	Approved	[5]
Prostate cancer	2C82.0	Approved	[5]
Renal cell carcinoma	2C90	Approved	[6]
Salivary gland squamous cell carcinoma	N.A.	Approved	[5]
Tuberous sclerosis	LD2D.2	Approved	[5]
Kidney cancer	2C90.0	Phase 3	[6]
Castration-resistant prostate carcinoma	N.A.	Investigative	[5]
Colon cancer	2B90.Z	Investigative	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[7]
Neuroblastoma	2D11.2	Investigative	[5]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[5]
Polycystic kidney disease	GB8Y	Investigative	[5]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[7]

Everolimus Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[13]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[7]

Everolimus Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]

Everolimus Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Loperamide FDA Label
• [4] Screening of an FDA-approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture Antimicrob Agents Chemother. 2014 Aug;58(8):4875-84.
• [5] Everolimus FDA Label
• [6] 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: 5889).
• [7] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [8] Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8.
• [9] In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos. 2008 Feb;36(2):268-75.
• [10] Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8.
• [11] Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81.
• [12] Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans. Drug Metab Dispos. 1995 Mar;23(3):354-62.
• [13] Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
• [14] Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations. Ther Drug Monit. 2015 Oct;37(5):675-80.
• [15] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.