Details of the Drug Combination

General Information of Drug Combination (ID: DC2HOHA)

• Drug Combination Name: Zonisamide + Bupropion
• Indication: Smoking Cessation; Status: Phase 3 [1]
• Component Drugs:
  Zonisamide (DM0DTF7): Small molecular drug
  Bupropion (DM5PCS7): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Zonisamide

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Alcohol use disorder	6C40.2	Approved	[2]
Bipolar disorder	6A60	Approved	[2]
Epilepsy	8A60-8A68	Approved	[3]

Zonisamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium channel unspecific (NaC)	TTRK8B9	NOUNIPROTAC	Blocker	[6]

Zonisamide Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]
Aldehyde oxidase (AOX)	DE8UGTM	A0A1V9IQJ2_CLOSG	Metabolism	[12]

Zonisamide Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tyrosine 3-monooxygenase (TH)	OT6ZORKP	TY3H_HUMAN	Increases Expression	[13]

Indication(s) of Bupropion

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Major depressive disorder	6A70.3	Approved	[4]
Obesity	5B81	Approved	[4]
Seasonal affective disorder	N.A.	Approved	[4]
Smoking dependence	6C4A.2	Approved	[5]

Bupropion Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Inhibitor	[15]
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Inhibitor	[15]

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	[16]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[17]

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	[18]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[20]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[21]

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	[22]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[14]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[23]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[14]
HLA class II histocompatibility antigen gamma chain (CD74)	OTO16X4Q	HG2A_HUMAN	Affects Expression	[24]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Expression	[24]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[14]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[14]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[14]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[23]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Expression	[25]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[14]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[24]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Response To Substance	[26]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response	[27]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Hydroxylation	[28]
Protein transport protein Sec24D (SEC24D)	OTXR3KC9	SC24D_HUMAN	Increases Response To Substance	[25]

References

• [1] ClinicalTrials.gov (NCT04388319) Zonisamide/Bupropion Effects on Switching to Electronic Cigarettes
• [2] Zonisamide 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: 7047).
• [4] Bupropion FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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• [8] Actual and Predicted Pharmacokinetic Interactions Between Anticonvulsants and Antiretrovirals.
• [9] Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data. Eur J Clin Pharmacol. 1998 Apr;54(2):177-83.
• [10] Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells. Biochim Biophys Acta. 1998 May 8;1380(3):297-304.
• [11] Carbamazepine pharmacokinetics are not affected by zonisamide: in vitro mechanistic study and in vivo clinical study in epileptic patients. Epilepsy Res. 2004 Nov;62(1):1-11.
• [12] The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J Pharm Pharmacol. 1997 Mar;49(3):253-6.
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• [14] 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.
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• [16] 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.
• [17] 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.
• [18] 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.
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• [20] Product Monograph of Wellbutrin SR(Bupropion Hydrochloride).
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.