Details of the Drug Combination

General Information of Drug Combination (ID: DC6QSHV)

• Drug Combination Name: Fosfomycin + Primidone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Fosfomycin (DMVGPMX): Small molecular drug
  Primidone (DM0WX6I): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 0.42
  Bliss Independence Score: 0.42
  Loewe Additivity Score: 13.99
  LHighest Single Agent (HSA) Score: 14.01

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fosfomycin

Disease Entry	ICD 11	Status	REF
Bacterial infection	1A00-1C4Z	Approved	[2]
Urinary tract infection	GC08	Approved	[3]

Fosfomycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial UDP-N-acetylglucosamine carboxyvinyltransferase (Bact murA)	TTICX3S	MURA_ECOLI	Inhibitor	[6]

Fosfomycin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[7]

Fosfomycin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[8]

Indication(s) of Primidone

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[4]
Epilepsy with generalized tonic-clonic seizures	N.A.	Approved	[5]
Focal epilepsy	N.A.	Approved	[5]

Primidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
GABA(A) receptor alpha-1 (GABRA1)	TT1MPAY	GBRA1_HUMAN	Antagonist	[9]

Primidone Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Primidone Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Decreases Expression	[13]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[14]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[14]
Glutathione hydrolase 7 (GGT7)	OTW4IO3I	GGT7_HUMAN	Increases ADR	[15]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Has nature already identified all useful antibacterial targets Curr Opin Microbiol. 2008 Oct;11(5):387-92.
• [3] Fosfomycin 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: 5338).
• [5] Primidone FDA Label
• [6] Evidence that the fosfomycin target Cys115 in UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is essential for product release. J Biol Chem. 2005 Feb 4;280(5):3757-63.
• [7] Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria. Antimicrob Agents Chemother. 1988 Oct;32(10):1552-6.
• [8] [Successful treatment of MRSA-associated glomerulonephritis with antibiotic therapy]. Nihon Jinzo Gakkai Shi. 2003;45(1):37-41.
• [9] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [10] Prescribrt's digital referenve - Primidone - Drug Summary.
• [11] Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther. 1999 Apr;24(2):87-92.
• [12] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [13] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [14] Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.