Details of the Drug Combination

General Information of Drug Combination (ID: DCHL0WN)

• Drug Combination Name: Lacosamide + Zileuton
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Lacosamide (DMVM6QR): Small molecular drug
  Zileuton (DMVRIC2): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 16.26
  Bliss Independence Score: 16.26
  Loewe Additivity Score: 32.46
  LHighest Single Agent (HSA) Score: 32.47

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lacosamide

Disease Entry	ICD 11	Status	REF
Convulsion	8A68.Z	Approved	[2]
Epilepsy	8A60-8A68	Approved	[3]
Diabetic neuropathy	8C0Z	Phase 3	[2]

Lacosamide Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.9 (SCN11A)	TTN9VTF	SCNBA_HUMAN	Inhibitor	[3]
Voltage-gated sodium channel (Nav)	TTIG65Q	NOUNIPROTAC	Inhibitor	[3]
Dihydropyrimidinase related protein 2 (DPYSL2)	TTZCW3T	DPYL2_HUMAN	Modulator	[6]

Lacosamide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[7]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[8]

Indication(s) of Zileuton

Disease Entry	ICD 11	Status	REF
Allergic asthma	CA23.0	Approved	[4]
Asthma	CA23	Approved	[5]
Intrinsic asthma	N.A.	Approved	[4]

Zileuton Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Arachidonate 5-lipoxygenase (5-LOX)	TT2J34L	LOX5_HUMAN	Inhibitor	[9]

Zileuton Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[10]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[10]

Zileuton Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[13]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[14]
Polyunsaturated fatty acid 5-lipoxygenase (ALOX5)	OT7FOIK2	LOX5_HUMAN	Decreases Activity	[15]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Increases Activity	[15]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[17]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[17]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Affects Response To Substance	[18]

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] 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: 7472).
• [3] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [4] Zileuton 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: 5297).
• [6] 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
• [7] Lacosamide: what can be expected from the next new antiepileptic drug? Epilepsy Curr. 2009 Sep-Oct;9(5):133-4.
• [8] Lacosamide therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit. 2013 Dec;35(6):849-52.
• [9] 5-lipoxygenase inhibitor zileuton attenuates ischemic brain damage: involvement of matrix metalloproteinase 9. Neurol Res. 2009 Oct;31(8):848-52.
• [10] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [11] Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218.
• [12] Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott-66193. Drug Metab Dispos. 1995 Oct;23(10):1163-74.
• [13] Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity. Bioorg Med Chem Lett. 2004 Nov 15;14(22):5591-4.
• [14] Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor. Drug Metab Dispos. 2003 Nov;31(11):1352-60.
• [15] Prostaglandins and leukotriene B4 are potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells. Biol Reprod. 1999 Jul;61(1):40-5.
• [16] Zileuton, a new efficient and safe systemic anti-acne drug. Dermatoendocrinol. 2009 May;1(3):188-92. doi: 10.4161/derm.1.3.8368.
• [17] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [18] 5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci. Pharmacogenet Genomics. 2009 Mar;19(3):244-7. doi: 10.1097/FPC.0b013e328326e0b1.