Details of the Drug Combination

General Information of Drug Combination (ID: DCKOFPV)

• Drug Combination Name: Zonisamide + Lamotrigine
• Indication: Epilepsy; Status: Phase 1 [1]
• Component Drugs:
  Zonisamide (DM0DTF7): Small molecular drug
  Lamotrigine (DM8SXYG): 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	[5]

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	[6]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[7]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[8]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]
Aldehyde oxidase (AOX)	DE8UGTM	A0A1V9IQJ2_CLOSG	Metabolism	[11]

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	[12]

Indication(s) of Lamotrigine

Disease Entry	ICD 11	Status	REF
Bipolar disorder	6A60	Approved	[4]
Epilepsy	8A60-8A68	Approved	[4]

Lamotrigine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.9 (SCN11A)	TTN9VTF	SCNBA_HUMAN	Blocker	[14]

Lamotrigine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[15]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[16]

Lamotrigine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 1A4 (UGT1A4)	DELOY3P	UD14_HUMAN	Metabolism	[19]

Lamotrigine Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[20]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[21]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Activity	[21]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[22]
Steroidogenic acute regulatory protein, mitochondrial (STAR)	OTFEZ5AI	STAR_HUMAN	Decreases Expression	[23]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[23]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[24]
Sodium channel protein type 2 subunit alpha (SCN2A)	OTUSYE4Z	SCN2A_HUMAN	Decreases Activity	[25]
Protein lin-28 homolog A (LIN28A)	OTJJBRCQ	LN28A_HUMAN	Decreases Expression	[23]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Activity	[26]
Adrenocorticotropic hormone receptor (MC2R)	OT6V19Y9	ACTHR_HUMAN	Increases Response To Substance	[27]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Increases Response To Substance	[27]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response To Substance	[27]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Increases Response To Substance	[27]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Response To Substance	[27]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Glutathionylation	[26]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Response To Substance	[28]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Glutathionylation	[26]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Glutathionylation	[26]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Glutathionylation	[26]

References

• [1] ClinicalTrials.gov (NCT04939675) Modification of Epilepsy Screen Questionnaire and Treatment Feasibility Evaluation
• [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] 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: 2622).
• [5] Antiepileptic drugs and relapse after epilepsy surgery. Epileptic Disord. 2008 Sep;10(3):193-8.
• [6] Pharmacokinetics and drug interactions with zonisamide. Epilepsia. 2007 Mar;48(3):435-41.
• [7] Actual and Predicted Pharmacokinetic Interactions Between Anticonvulsants and Antiretrovirals.
• [8] Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data. Eur J Clin Pharmacol. 1998 Apr;54(2):177-83.
• [9] 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.
• [10] 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.
• [11] The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J Pharm Pharmacol. 1997 Mar;49(3):253-6.
• [12] [The discovery of an antiparkinsonian drug, zonisamide]. Rinsho Shinkeigaku. 2010 Feb;50(2):67-73. doi: 10.5692/clinicalneurol.50.67.
• [13] Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation. Drug Metab Dispos. 2007 Mar;35(3):419-27.
• [14] The effects of lamotrigine on the acquisition and expression of morphine-induced place preference in mice. Pak J Biol Sci. 2009 Jan 1;12(1):33-9.
• [15] Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008 Dec;55(8):1364-75.
• [16] Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol. 2012 Mar 15;83(6):805-14.
• [17] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [18] Variation in glucuronidation of lamotrigine in human liver microsomes. Xenobiotica. 2009 May;39(5):355-63.
• [19] Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009 Nov;39(11):826-35.
• [20] Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. Pharmacogenet Genomics. 2008 May;18(5):390-402. doi: 10.1097/FPC.0b013e3282f85e36.
• [21] Effects of anticonvulsants on human p450c17 (17alpha-hydroxylase/17,20 lyase) and 3beta-hydroxysteroid dehydrogenase type 2. Epilepsia. 2005 Mar;46(3):444-8.
• [22] Inhibition of human aromatase complex (CYP19) by antiepileptic drugs. Toxicol In Vitro. 2008 Feb;22(1):146-53.
• [23] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [24] Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents. Epilepsy Res. 2005 Jan;63(1):17-25. doi: 10.1016/j.eplepsyres.2004.10.002. Epub 2004 Dec 8.
• [25] Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. Pflugers Arch. 2001 Jan;441(4):425-33. doi: 10.1007/s004240000448.
• [26] Bioactivation of lamotrigine in vivo in rat and in vitro in human liver microsomes, hepatocytes, and epidermal keratinocytes: characterization of thioether conjugates by liquid chromatography/mass spectrometry and high field nuclear magnetic resonance spectroscopy. Chem Res Toxicol. 2010 Jan;23(1):159-70. doi: 10.1021/tx9003243.
• [27] Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression. J Clin Psychiatry. 2010 May;71(5):599-605. doi: 10.4088/JCP.08m04632gre. Epub 2009 Dec 15.
• [28] Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics. 2010 Mar;11(3):349-56. doi: 10.2217/pgs.09.162.