Details of the Drug Combination

General Information of Drug Combination (ID: DCWDV5Y)

• Drug Combination Name: Ethambutol + Primidone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Ethambutol (DMR87LC): Small molecular drug
  Primidone (DM0WX6I): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 15.75
  Bliss Independence Score: 15.75
  Loewe Additivity Score: 30.25
  LHighest Single Agent (HSA) Score: 30.27

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ethambutol

Disease Entry	ICD 11	Status	REF
Pulmonary tuberculosis	1B10.Z	Approved	[2]

Ethambutol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mycobacterium Arabinosyltransferase C (MycB embC)	TT1Q8GP	EMBC_MYCTU	Inhibitor	[5]

Ethambutol Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[6]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[6]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[6]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[6]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[7]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Secretion	[8]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[9]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[9]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[9]
Granzyme B (GZMB)	OTPPVIRS	GRAB_HUMAN	Increases Secretion	[8]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[9]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[9]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Increases Secretion	[8]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[9]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[7]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[9]

Indication(s) of Primidone

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[3]
Epilepsy with generalized tonic-clonic seizures	N.A.	Approved	[4]
Focal epilepsy	N.A.	Approved	[4]

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	[10]

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	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[12]

Primidone Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases ADR	[13]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Activity	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[9]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Decreases Expression	[9]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[16]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[16]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[17]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[9]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Increases ADR	[13]
Glutathione hydrolase 7 (GGT7)	OTW4IO3I	GGT7_HUMAN	Increases ADR	[13]

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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 5338).
• [4] Primidone FDA Label
• [5] The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2009 Oct;53(10):4138-46.
• [6] Inhibition of cytochrome P450 by ethambutol in human liver microsomes. Toxicol Lett. 2014 Aug 17;229(1):33-40.
• [7] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [8] Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury. Chem Res Toxicol. 2016 Nov 21;29(11):1793-1795. doi: 10.1021/acs.chemrestox.6b00393. Epub 2016 Nov 9.
• [9] 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.
• [10] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [11] Prescribrt's digital referenve - Primidone - Drug Summary.
• [12] Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther. 1999 Apr;24(2):87-92.
• [13] 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.
• [14] Antiepileptic drugs: impacts on human serum paraoxonase-1. J Biochem Mol Toxicol. 2017 Jun;31(6).
• [15] 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.
• [16] 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.
• [17] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.