Details of the Drug Combination

General Information of Drug Combination (ID: DC4OABL)

• Drug Combination Name: Fosphenytoin + Clonazepam
• Indication: Status Epilepticus; Status: Phase 3 [1]
• Component Drugs:
  Fosphenytoin (DMOX3LB): Small molecular drug
  Clonazepam (DMTO13J): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fosphenytoin

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[2]

Fosphenytoin 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	[5]

Fosphenytoin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[7]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[8]

Indication(s) of Clonazepam

Disease Entry	ICD 11	Status	REF
Absence epilepsy	N.A.	Approved	[3]
Epilepsy	8A60-8A68	Approved	[4]
Panic disorder	6B01	Approved	[3]
Seizure disorder	8A6Z	Phase 2	[4]

Clonazepam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gamma-aminobutyric acid receptor (GAR)	TTNJYV2	NOUNIPROTAC	Agonist	[9]

Clonazepam Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[11]
Oxygen-insensitive NADPH nitroreductase B (nfsB)	DE0QLUZ	NFSB_ECOLI	Metabolism	[12]

References

• [1] ClinicalTrials.gov (NCT01870024) Comparison Between Lorazepam, Clonazepam and Clonazepam + Fosphenytoin for the Treatment of Out-of-hospital Generalized Status Epilepticus
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Clonazepam FDA Label
• [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: 6963).
• [5] Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs. 2009;23(7):555-68.
• [6] Basic review of the cytochrome p450 system. J Adv Pract Oncol. 2013 Jul;4(4):263-8.
• [7] 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.
• [8] CYP2C9, CYP2C19, and ABCB1 genotype and hospitalization for phenytoin toxicity. J Clin Pharmacol. 2009 Dec;49(12):1483-7.
• [9] Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
• [10] Identification of the human and animal hepatic cytochromes P450 involved in clonazepam metabolism. Fundam Clin Pharmacol. 1993;7(2):69-75.
• [11] Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam. Drug Metab Lett. 2007 Jan;1(1):3-5.
• [12] Characterization of Escherichia coli nitroreductase NfsB in the metabolism of nitrobenzodiazepines. Biochem Pharmacol. 2009 Jul 1;78(1):96-103.