Details of the Drug Combination

General Information of Drug Combination (ID: DC8DF9Y)

• Drug Combination Name: Naltrexone + Idarubicin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Naltrexone (DMUL45H): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 8.27
  Bliss Independence Score: 8.27
  Loewe Additivity Score: 16.44
  LHighest Single Agent (HSA) Score: 16.44

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Naltrexone

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Chronic alcoholism	6C40.2Z	Approved	[3]
Crohn disease	DD70	Approved	[4]
Gastroparesis	DA41.00	Approved	[4]
Inflammatory bowel disease	DD72	Approved	[4]
Obesity	5B81	Approved	[4]
Ulcerative colitis	DD71	Approved	[4]
Human immunodeficiency virus infection	1C62	Phase 4	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[6]
Chronic pain	MG30	Investigative	[4]

Naltrexone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Antagonist	[9]

Naltrexone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[10]

Naltrexone Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Activity	[11]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[12]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[12]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Affects Response To Substance	[9]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[9]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[13]
Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)	OTAOZIGX	GBRB2_HUMAN	Affects Response To Substance	[14]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[14]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Response To Substance	[14]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[7]
Acute myeloid leukaemia	2A60	Approved	[8]
Adult acute monocytic leukemia	N.A.	Approved	[7]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[7]
Leukemia	N.A.	Approved	[7]

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	[16]

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	[17]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[18]

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	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]

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	[15]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[20]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[15]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[21]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[15]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[22]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[23]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[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] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074918.
• [4] Naltrexone FDA Label
• [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: 1639).
• [6] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [7] Idarubicin FDA Label
• [8] 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).
• [9] An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008 Feb;65(2):135-44.
• [10] In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat. Biochem Pharmacol. 2008 Sep 1;76(5):672-9.
• [11] Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-4.
• [12] Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients. J Clin Endocrinol Metab. 1995 May;80(5):1739-42. doi: 10.1210/jcem.80.5.7745028.
• [13] Association between the Stin2 VNTR polymorphism of the serotonin transporter gene and treatment outcome in alcohol-dependent patients. Alcohol Alcohol. 2008 Sep-Oct;43(5):516-22. doi: 10.1093/alcalc/agn048. Epub 2008 Jun 14.
• [14] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.
• [15] 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.
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [17] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [18] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [19] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [20] 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.
• [21] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [22] 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.
• [23] 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.