Details of the Drug Combination

General Information of Drug Combination (ID: DCMKAGT)

• Drug Combination Name: Armodafinil + Mephenytoin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Armodafinil (DMGB035): Small molecular drug
  Mephenytoin (DM5UGDK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 7.35
  Bliss Independence Score: 7.35
  Loewe Additivity Score: 21.44
  LHighest Single Agent (HSA) Score: 21.44

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Armodafinil

Disease Entry	ICD 11	Status	REF
Malignant glioma	2A00.0	Approved	[2]
Methamphetamine dependence	6C46.2	Approved	[2]
Narcolepsy	7A20	Approved	[2]
Pain	MG30-MG3Z	Approved	[2]
Pediatric cancer	2A00-2F9Z	Approved	[3]
Postpoliomyelitis syndrome	N.A.	Approved	[2]
Traumatic brain injury	NA07.Z	Approved	[2]

Armodafinil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor alpha-1D (ADRA1D)	TT34BHT	ADA1D_HUMAN	Agonist	[5]

Armodafinil Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[7]

Indication(s) of Mephenytoin

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

Mephenytoin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.5 (SCN5A)	TTZOVE0	SCN5A_HUMAN	Blocker	[8]

Mephenytoin Interacts with 9 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[12]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[12]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[15]

Mephenytoin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Methylation	[16]

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] Armodafinil FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 7223).
• [5] Mechanisms of modafinil: A review of current research. Neuropsychiatr Dis Treat. 2007 June; 3(3): 349-364.
• [6] Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects. Clin Pharmacokinet. 2008;47(1):61-74.
• [7] Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123-37.
• [8] Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs. 2009;23(7):555-68.
• [9] Species differences in stereoselective metabolism of mephenytoin by cytochrome P450 (CYP2C and CYP3A). J Pharmacol Exp Ther. 1993 Jan;264(1):89-94.
• [10] Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms. Br J Clin Pharmacol. 1999 Aug;48(2):158-67.
• [11] Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet. 2004 Apr;19(2):83-95.
• [12] Cytochrome P450 metabolic dealkylation of nine N-nitrosodialkylamines by human liver microsomes. Carcinogenesis. 1996 Sep;17(9):2029-34.
• [13] Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans. Biochemistry. 1994 Feb 22;33(7):1743-52.
• [14] 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.
• [15] Cytochromes P450 mediating the N-demethylation of amitriptyline. Br J Clin Pharmacol. 1997 Feb;43(2):137-44.
• [16] Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos. 2002 Dec;30(12):1311-9.