Details of the Drug Combination

General Information of Drug Combination (ID: DCEVL3P)

• Drug Combination Name: Bupropion + Naltrexone
• Indication: Obesity; Status: Phase 1 [1]
• Component Drugs:
  Bupropion (DM5PCS7): Small molecular drug
  Naltrexone (DMUL45H): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bupropion

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Major depressive disorder	6A70.3	Approved	[2]
Obesity	5B81	Approved	[2]
Seasonal affective disorder	N.A.	Approved	[2]
Smoking dependence	6C4A.2	Approved	[3]

Bupropion Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Inhibitor	[9]
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Inhibitor	[9]

Bupropion Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]

Bupropion Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[15]

Bupropion Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Hydrolysis	[16]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[8]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[17]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[8]
HLA class II histocompatibility antigen gamma chain (CD74)	OTO16X4Q	HG2A_HUMAN	Affects Expression	[18]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Expression	[18]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[8]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[8]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[8]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[17]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Expression	[19]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[8]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[18]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Response To Substance	[20]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response	[21]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Hydroxylation	[22]
Protein transport protein Sec24D (SEC24D)	OTXR3KC9	SC24D_HUMAN	Increases Response To Substance	[19]

Indication(s) of Naltrexone

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[3]
Chronic alcoholism	6C40.2Z	Approved	[4]
Crohn disease	DD70	Approved	[5]
Gastroparesis	DA41.00	Approved	[5]
Inflammatory bowel disease	DD72	Approved	[5]
Obesity	5B81	Approved	[5]
Ulcerative colitis	DD71	Approved	[5]
Human immunodeficiency virus infection	1C62	Phase 4	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Chronic pain	MG30	Investigative	[5]

Naltrexone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Antagonist	[23]

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	[24]

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	[25]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[26]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[26]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Affects Response To Substance	[23]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[23]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[27]
Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)	OTAOZIGX	GBRB2_HUMAN	Affects Response To Substance	[28]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[28]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Response To Substance	[28]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Binge Drinking	DC6OC31	N. A.	Phase 2	[29]
Smoking	DCQFAHU	N. A.	Phase 1	[30]

References

• [1] A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring). 2013 May;21(5):935-43.
• [2] Bupropion FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074918.
• [5] Naltrexone 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: 1639).
• [7] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [8] Bupropion, an atypical antidepressant, induces endoplasmic reticulum stress and caspase-dependent cytotoxicity in SH-SY5Y cells. Toxicology. 2011 Jul 11;285(1-2):1-7. doi: 10.1016/j.tox.2011.02.006. Epub 2011 Feb 24.
• [9] Clinically relevant drug interactions with new generation antidepressants and antipsychotics. Ther Umsch. 2009 Jun;66(6):485-92.
• [10] Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. Biol Pharm Bull. 2008 Feb;31(2):231-4.
• [11] Role of transporter-mediated efflux in the placental biodisposition of bupropion and its metabolite, OH-bupropion. Biochem Pharmacol. 2010 Oct 1;80(7):1080-6.
• [12] In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation. Biochem Pharmacol. 2017 Jan 1;123:85-96.
• [13] Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos. 2000 Oct;28(10):1222-30.
• [14] Product Monograph of Wellbutrin SR(Bupropion Hydrochloride).
• [15] Laparoscopic Roux-en-Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates. Basic Clin Pharmacol Toxicol. 2019 Aug;125(2):123-132.
• [16] The monoterpenoids citral and geraniol are moderate inhibitors of CYP2B6 hydroxylase activity. Chem Biol Interact. 2008 Aug 11;174(3):141-6. doi: 10.1016/j.cbi.2008.06.003. Epub 2008 Jun 20.
• [17] Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells. Neurosci Lett. 2006 Mar 13;395(3):185-90. doi: 10.1016/j.neulet.2005.10.096. Epub 2005 Dec 1.
• [18] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [19] Pharmacological Chaperones of the Dopamine Transporter Rescue Dopamine Transporter Deficiency Syndrome Mutations in Heterologous Cells. J Biol Chem. 2016 Oct 14;291(42):22053-22062. doi: 10.1074/jbc.M116.749119. Epub 2016 Aug 23.
• [20] Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation. Addiction. 2012 Jan;107(1):178-87. doi: 10.1111/j.1360-0443.2011.03534.x. Epub 2011 Sep 21.
• [21] Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials. Nicotine Tob Res. 2007 Dec;9(12):1251-7. doi: 10.1080/14622200701705027.
• [22] Overexpression of the constitutive androstane receptor and shaken 3D-culturing increase biotransformation and oxidative phosphorylation and sensitivity to mitochondrial amiodarone toxicity of HepaRG cells. Toxicol Appl Pharmacol. 2020 Jul 15;399:115055. doi: 10.1016/j.taap.2020.115055. Epub 2020 May 16.
• [23] 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.
• [24] 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.
• [25] Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-4.
• [26] 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.
• [27] 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.
• [28] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.
• [29] ClinicalTrials.gov (NCT02842073) An Open Label Trial of Bupropion and Naltrexone for Binge Drinking
• [30] ClinicalTrials.gov (NCT00129246) Low-Dose Naltrexone Combined With Bupropion to Stop Smoking With Less Weight Gain