Details of the Drug Combination

General Information of Drug Combination (ID: DC9XDVL)

• Drug Combination Name: Chlorzoxazone + Furazolidone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Chlorzoxazone (DMCYVDT): Small molecular drug
  Furazolidone (DM3P6V7): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 4.36
  Bliss Independence Score: 4.36
  Loewe Additivity Score: 4.96
  LHighest Single Agent (HSA) Score: 5

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Chlorzoxazone

Disease Entry	ICD 11	Status	REF
Acute pain	MG31	Approved	[2]

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	[5]

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	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[9]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[10]

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	[11]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[12]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Affects Metabolism	[4]

Indication(s) of Furazolidone

Disease Entry	ICD 11	Status	REF
Diarrhea	ME05.1	Approved	[3]

Furazolidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Deoxyribonucleic acid (Bact DNA)	TTS1W4A	NOUNIPROTAC	Modulator	[13]

Furazolidone Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Expression	[14]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[14]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[16]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[14]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Increases Expression	[16]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[15]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[14]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Expression	[14]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[15]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[15]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Increases Expression	[16]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[15]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Increases ADR	[18]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases ADR	[18]

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] 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).
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 011270.
• [4] 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.
• [5] Chlorzoxazone inhibits contraction of rat thoracic aorta. Eur J Pharmacol. 2006 Sep 18;545(2-3):161-6.
• [6] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [7] Inhibitory monoclonal antibodies to human cytochrome P450 1A2: analysis of phenacetin O-deethylation in human liver. Pharmacogenetics. 1998 Oct;8(5):375-82.
• [8] 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.
• [9] Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041-7.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Interaction of furazolidone with DNA. Biochim Biophys Acta. 1975 Aug 21;402(2):161-5.
• [14] Involvement of the activation of Nrf2/HO-1, p38 MAPK signaling pathways and endoplasmic reticulum stress in furazolidone induced cytotoxicity and S phase arrest in human hepatocyte L02 cells: modulation of curcumin. Toxicol Mech Methods. 2017 Mar;27(3):165-172. doi: 10.1080/15376516.2016.1273424. Epub 2017 Jan 8.
• [15] P21(Waf1/Cip1) plays a critical role in furazolidone-induced apoptosis in HepG2 cells through influencing the caspase-3 activation and ROS generation. Food Chem Toxicol. 2016 Feb;88:1-12. doi: 10.1016/j.fct.2015.12.004. Epub 2015 Dec 11.
• [16] Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells. J Appl Toxicol. 2013 Dec;33(12):1500-5. doi: 10.1002/jat.2829. Epub 2012 Oct 30.
• [17] The Effect of GADD45a on Furazolidone-Induced S-Phase Cell-Cycle Arrest in Human Hepatoma G2 Cells. J Biochem Mol Toxicol. 2015 Oct;29(10):489-495. doi: 10.1002/jbt.21719. Epub 2015 Jun 11.
• [18] 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.