Details of the Drug Combination

General Information of Drug Combination (ID: DC0PPRT)

• Drug Combination Name: Disulfiram + Naltrexone
• Indication: Alcohol-Related Disorders; Status: Phase 1 [1]
• Component Drugs:
  Disulfiram (DMCL2OK): Small molecular drug
  Naltrexone (DMUL45H): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Disulfiram

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[4]

Disulfiram Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV papain-like proteinase (PL-PRO)	TTYJOLE	R1AB_CVEMC (854-2740)	Inhibitor	[4]
Fatty aldehyde dehydrogenase (ALDH3A2)	TTB6UM0	AL3A2_HUMAN	Inhibitor	[10]
COVID-19 papain-like proteinase (PL-PRO)	TTNHMO8	R1AB_SARS2 (819-2763)	Inhibitor	[3]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[4]

Disulfiram Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[13]

Disulfiram Interacts with 73 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Increases ADR	[14]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Decreases Activity	[15]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[16]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Activity	[17]
Metallothionein-2 (MT2A)	OTHOACHD	MT2_HUMAN	Increases Expression	[18]
Metallothionein-1F (MT1F)	OTZVUYG1	MT1F_HUMAN	Increases Expression	[18]
Metallothionein-1B (MT1B)	OTUA4FFH	MT1B_HUMAN	Increases Expression	[18]
Metallothionein-1G (MT1G)	OTAV1OCR	MT1G_HUMAN	Increases Expression	[18]
DNA replication licensing factor MCM5 (MCM5)	OTAHLB62	MCM5_HUMAN	Decreases Expression	[18]
DNA replication licensing factor MCM2 (MCM2)	OTGGORIQ	MCM2_HUMAN	Decreases Expression	[18]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Increases Expression	[18]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Increases Expression	[9]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[9]
Transcription factor MafK (MAFK)	OTZJUE4P	MAFK_HUMAN	Increases Expression	[9]
Glutathione reductase, mitochondrial (GSR)	OTM2TUYM	GSHR_HUMAN	Increases Expression	[9]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Increases Expression	[9]
Ferritin light chain (FTL)	OTYQA8A6	FRIL_HUMAN	Increases Expression	[9]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[9]
Extracellular superoxide dismutase (SOD3)	OTIOZQAB	SODE_HUMAN	Increases Expression	[9]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[9]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[9]
Microsomal glutathione S-transferase 1 (MGST1)	OTGN1KVZ	MGST1_HUMAN	Increases Expression	[9]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Expression	[9]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Increases Expression	[9]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[9]
Glutathione peroxidase 3 (GPX3)	OT6PK94R	GPX3_HUMAN	Increases Expression	[9]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Increases Expression	[9]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Expression	[9]
NADP-dependent malic enzyme (ME1)	OTSVEUQE	MAOX_HUMAN	Increases Expression	[9]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[9]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Increases Expression	[9]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Expression	[9]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Expression	[9]
Prostaglandin reductase 1 (PTGR1)	OTMAR351	PTGR1_HUMAN	Increases Expression	[9]
SPRY domain-containing SOCS box protein 1 (SPSB1)	OTGY26U4	SPSB1_HUMAN	Increases Expression	[9]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[9]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Increases Expression	[9]
Retinal dehydrogenase 2 (ALDH1A2)	OTJB560Z	AL1A2_HUMAN	Decreases Activity	[19]
Aldehyde dehydrogenase, mitochondrial (ALDH2)	OTKJ9I3N	ALDH2_HUMAN	Decreases Activity	[19]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[20]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[21]
Aldehyde dehydrogenase 1A1 (ALDH1A1)	OTCUWZKB	AL1A1_HUMAN	Decreases Expression	[22]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[23]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Secretion	[24]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[24]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[25]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[26]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[27]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[28]
Integrin alpha-M (ITGAM)	OTAG6HWU	ITAM_HUMAN	Increases Expression	[24]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Secretion	[24]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[27]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[29]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Increases Degradation	[30]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Decreases Expression	[24]
Cyclic AMP-dependent transcription factor ATF-3 (ATF3)	OTC1UOHP	ATF3_HUMAN	Increases Expression	[31]
Cystathionine gamma-lyase (CTH)	OTC90LA0	CGL_HUMAN	Increases Expression	[22]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Affects Expression	[24]
C-C chemokine receptor type 2 (CCR2)	OTQ7T10J	CCR2_HUMAN	Increases Expression	[24]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[32]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[28]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[32]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Decreases Cleavage	[33]
Hemoglobin subunit gamma-2 (HBG2)	OT4J48JJ	HBG2_HUMAN	Increases Expression	[34]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[28]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[25]
Scavenger receptor cysteine-rich type 1 protein M130 (CD163)	OT2E32LN	C163A_HUMAN	Decreases Expression	[24]
Metallothionein-1M (MT1M)	OTVT8PLU	MT1M_HUMAN	Increases Expression	[31]
C-type lectin domain family 7 member A (CLEC7A)	OTRTBH27	CLC7A_HUMAN	Increases Expression	[24]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[35]
Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1)	OTAYZZE6	AL3A1_HUMAN	Increases Metabolism	[36]
Ataxin-3 (ATXN3)	OTJVVGKT	ATX3_HUMAN	Increases Response To Substance	[37]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Response To Substance	[38]

Indication(s) of Naltrexone

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Chronic alcoholism	6C40.2Z	Approved	[5]
Crohn disease	DD70	Approved	[6]
Gastroparesis	DA41.00	Approved	[6]
Inflammatory bowel disease	DD72	Approved	[6]
Obesity	5B81	Approved	[6]
Ulcerative colitis	DD71	Approved	[6]
Human immunodeficiency virus infection	1C62	Phase 4	[7]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[8]
Chronic pain	MG30	Investigative	[6]

Naltrexone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Antagonist	[39]

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	[40]

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	[41]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[42]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[42]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Affects Response To Substance	[39]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[39]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[43]
Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)	OTAOZIGX	GBRB2_HUMAN	Affects Response To Substance	[44]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[44]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Response To Substance	[44]

References

• [1] ClinicalTrials.gov (NCT00142844) Combination of Disulfiram Plus Naltrexone to Treat Both Cocaine- and Alcohol-dependent Individuals - 1
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. 2020 Apr 9.
• [4] Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020 Mar;19(3):149-150.
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074918.
• [6] Naltrexone 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: 1639).
• [8] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [9] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [10] Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006 Sep;111(3):855-76.
• [11] Interaction of disulfiram with antiretroviral medications: efavirenz increases while atazanavir decreases disulfiram effect on enzymes of alcohol metabolism. Am J Addict. 2014 Mar-Apr;23(2):137-44.
• [12] Identification of the human P-450 enzymes responsible for the sulfoxidation and thiono-oxidation of diethyldithiocarbamate methyl ester: role of P-450 enzymes in disulfiram bioactivation. Alcohol Clin Exp Res. 1998 Sep;22(6):1212-9.
• [13] Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administration in humans. J Pharmacol Exp Ther. 1999 Oct;291(1):213-9.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [15] Hypotension with anesthesia in disulfiram-treated patients. Anesthesiology. 1979 Oct;51(4):366-8.
• [16] Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol. 1991 Mar-Apr;4(2):168-79.
• [17] The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1). Mol Pharmacol. 2004 Mar;65(3):675-84.
• [18] High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res. 2009 Oct 1;15(19):6070-8.
• [19] The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by Aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chem Biol Interact. 2012 Jan 5;195(1):52-60.
• [20] Species-specific differences in the inhibition of human and zebrafish 11beta-hydroxysteroid dehydrogenase 2 by thiram and organotins. Toxicology. 2012 Nov 15;301(1-3):72-8.
• [21] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [22] The interaction of disulfiram and H(2)S metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth. Toxicol Appl Pharmacol. 2021 Sep 1;426:115642. doi: 10.1016/j.taap.2021.115642. Epub 2021 Jul 6.
• [23] Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
• [24] Comparative study of the effects of ziram and disulfiram on human monocyte-derived macrophage functions and polarization: involvement of zinc. Cell Biol Toxicol. 2021 Jun;37(3):379-400. doi: 10.1007/s10565-020-09540-6. Epub 2020 Jul 25.
• [25] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [26] Disulfiram metabolites permanently inactivate the human multidrug resistance P-glycoprotein. Mol Pharm. 2004 Nov-Dec;1(6):426-33. doi: 10.1021/mp049917l.
• [27] Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression. J Biochem Mol Biol. 2007 Nov 30;40(6):1069-76. doi: 10.5483/bmbrep.2007.40.6.1069.
• [28] Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006 Nov 1;66(21):10425-33. doi: 10.1158/0008-5472.CAN-06-2126.
• [29] Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition. Cancers (Basel). 2021 Nov 14;13(22):5699. doi: 10.3390/cancers13225699.
• [30] Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis. 2014 Mar;35(3):692-702. doi: 10.1093/carcin/bgt366. Epub 2013 Nov 5.
• [31] Identification of novel activators of the metal responsive transcription factor (MTF-1) using a gene expression biomarker in a microarray compendium. Metallomics. 2020 Sep 23;12(9):1400-1415. doi: 10.1039/d0mt00071j.
• [32] Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochem Pharmacol. 2007 Jan 1;73(1):25-33. doi: 10.1016/j.bcp.2006.08.016. Epub 2006 Aug 26.
• [33] Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis. Inflamm Res. 2021 May;70(5):543-552. doi: 10.1007/s00011-021-01457-y. Epub 2021 Apr 13.
• [34] Cytochrome P(450)-dependent toxic effects of primaquine on human erythrocytes. Toxicol Appl Pharmacol. 2009 Nov 15;241(1):14-22. doi: 10.1016/j.taap.2009.07.012. Epub 2009 Jul 17.
• [35] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [36] Contribution of aldehyde dehydrogenase 3A1 to disulfiram penetration through monolayers consisting of cultured human corneal epithelial cells. Biol Pharm Bull. 2008 Jul;31(7):1444-8. doi: 10.1248/bpb.31.1444.
• [37] Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3. J Toxicol Sci. 2019;44(8):535-542. doi: 10.2131/jts.44.535.
• [38] Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos. 2011 Aug;39(8):1388-95. doi: 10.1124/dmd.110.037077. Epub 2011 May 3.
• [39] 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.
• [40] 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.
• [41] Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-4.
• [42] 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.
• [43] 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.
• [44] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.