Details of the Drug Combination

General Information of Drug Combination (ID: DCEKV8B)

• Drug Combination Name: Ethambutol + Chlorzoxazone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Ethambutol (DMR87LC): Small molecular drug
  Chlorzoxazone (DMCYVDT): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 2.98
  Bliss Independence Score: 2.98
  Loewe Additivity Score: 3.79
  LHighest Single Agent (HSA) Score: 3.79

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	[4]

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	[5]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[5]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[5]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[5]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[6]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Secretion	[7]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[8]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[8]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[8]
Granzyme B (GZMB)	OTPPVIRS	GRAB_HUMAN	Increases Secretion	[7]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[8]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[8]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Increases Secretion	[7]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[8]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[6]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[8]

Indication(s) of Chlorzoxazone

Disease Entry	ICD 11	Status	REF
Acute pain	MG31	Approved	[3]

Chlorzoxazone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcium-activated potassium channel (KCN)	TTMNI76	NOUNIPROTAC	Activator	[10]

Chlorzoxazone Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[15]

Chlorzoxazone Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4)	OTQKQ346	KCNN4_HUMAN	Increases Activity	[16]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[17]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Affects Metabolism	[9]

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: 2322).
• [4] The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2009 Oct;53(10):4138-46.
• [5] Inhibition of cytochrome P450 by ethambutol in human liver microsomes. Toxicol Lett. 2014 Aug 17;229(1):33-40.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism. Clin Pharmacol Ther. 2003 Nov;74(5):468-74. doi: 10.1016/j.clpt.2003.07.001.
• [10] Chlorzoxazone inhibits contraction of rat thoracic aorta. Eur J Pharmacol. 2006 Sep 18;545(2-3):161-6.
• [11] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [12] Inhibitory monoclonal antibodies to human cytochrome P450 1A2: analysis of phenacetin O-deethylation in human liver. Pharmacogenetics. 1998 Oct;8(5):375-82.
• [13] Prediction of human liver microsomal oxidations of 7-ethoxycoumarin and chlorzoxazone with kinetic parameters of recombinant cytochrome P-450 enzymes. Drug Metab Dispos. 1999 Nov;27(11):1274-80.
• [14] Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041-7.
• [15] Wild-type CYP102A1 as a biocatalyst: turnover of drugs usually metabolised by human liver enzymes. J Biol Inorg Chem. 2007 Mar;12(3):313-23.
• [16] Functional and molecular identification of intermediate-conductance Ca(2+)-activated K(+) channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol. 2004 Jul;287(1):C125-34. doi: 10.1152/ajpcell.00488.2003. Epub 2004 Feb 25.
• [17] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.