Details of the Drug Combination

General Information of Drug Combination (ID: DCEB31F)

• Drug Combination Name: Tetracycline + Chlorzoxazone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Tetracycline (DMZA017): Small molecular drug
  Chlorzoxazone (DMCYVDT): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.7
  Bliss Independence Score: 3.7
  Loewe Additivity Score: 4.43
  LHighest Single Agent (HSA) Score: 4.48

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tetracycline

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Actinomycosis	N.A.	Approved	[2]
Acute gonococcal cervicitis	N.A.	Approved	[2]
Acute gonococcal epididymo-orchitis	N.A.	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Bronchitis	CA20	Approved	[2]
Brucellosis	N.A.	Approved	[2]
Lymphogranuloma venereum	N.A.	Approved	[2]
Ornithosis	N.A.	Approved	[2]
Pneumonia	CA40	Approved	[2]
Q fever	N.A.	Approved	[2]
Relapsing fever	N.A.	Approved	[2]
Rickettsialpox	N.A.	Approved	[2]
Rocky mountain spotted fever	N.A.	Approved	[2]
Syphilis	N.A.	Approved	[2]
Trachoma	N.A.	Approved	[2]
Typhus	N.A.	Approved	[2]
Urinary tract infection	GC08	Approved	[2]
Yaws	N.A.	Approved	[2]
Pelvic inflammatory disease	GA05	Investigative	[2]
Sinusitis	CA0A.Z	Investigative	[2]

Tetracycline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Staphylococcus 30S ribosomal subunit (Stap-coc pbp2)	TTQ8KVI	F4NA87_STAAU	Binder	[6]

Tetracycline Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]
Organic anion transporter 2 (SLC22A7)	DT0OC1Q	S22A7_HUMAN	Substrate	[9]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[9]
Organic anion transporter 4 (SLC22A11)	DT06JWZ	S22AB_HUMAN	Substrate	[9]

Tetracycline Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 7 (SLC22A7)	OTKTNH1W	S22A7_HUMAN	Increases Transport	[10]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Uptake	[9]
Glutathione S-transferase Mu 3 (GSTM3)	OTLA2WJT	GSTM3_HUMAN	Decreases Activity	[11]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[5]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[5]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[5]
AP-1 complex subunit sigma-1A (AP1S1)	OTQ2H8DN	AP1S1_HUMAN	Decreases Expression	[5]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[5]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[5]
Alternative prion protein (PRNP)	OTE85L1Q	APRIO_HUMAN	Affects Binding	[12]
Claudin-11 (CLDN11)	OTNN6UTL	CLD11_HUMAN	Decreases Expression	[13]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Decreases Activity	[14]
Neutrophil collagenase (MMP8)	OTZXH19L	MMP8_HUMAN	Decreases Activity	[14]
Integrin alpha-3 (ITGA3)	OTBCH21D	ITA3_HUMAN	Decreases Expression	[13]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[15]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[15]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Decreases Activity	[14]
Gap junction alpha-8 protein (GJA8)	OTZCPRKD	CXA8_HUMAN	Decreases Expression	[13]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Decreases Expression	[16]
Claudin-15 (CLDN15)	OT9K0KI7	CLD15_HUMAN	Decreases Expression	[13]
Claudin-8 (CLDN8)	OT7IIWXG	CLD8_HUMAN	Decreases Expression	[13]
Claudin-2 (CLDN2)	OTRF3D6Y	CLD2_HUMAN	Decreases Expression	[13]
Claudin-10 (CLDN10)	OT2CVAKY	CLD10_HUMAN	Decreases Expression	[13]
Peroxisomal bifunctional enzyme (EHHADH)	OTBAAHL5	ECHP_HUMAN	Decreases Expression	[16]
Neurogenic locus notch homolog protein 4 (NOTCH4)	OTBCHB61	NOTC4_HUMAN	Decreases Expression	[13]
Gap junction delta-2 protein (GJD2)	OTDR288R	CXD2_HUMAN	Decreases Expression	[13]
Neurogenic locus notch homolog protein 3 (NOTCH3)	OTMVVA7F	NOTC3_HUMAN	Decreases Expression	[13]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Increases Export	[9]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[17]
Organic anion transporter 7 (SLC22A9)	OTO4BJCC	S22A9_HUMAN	Increases Export	[9]

Indication(s) of Chlorzoxazone

Disease Entry	ICD 11	Status	REF
Acute pain	MG31	Approved	[4]

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	[19]

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	[20]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[21]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[22]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[22]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[23]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[24]

Chlorzoxazone Interacts with 2 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	[25]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Affects Metabolism	[18]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Tetracycline FDA Label
• [3] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [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: 2322).
• [5] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [6] The glycylcyclines: a comparative review with the tetracyclines. Drugs. 2004;64(1):63-88.
• [7] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [8] Arginine-482 is not essential for transport of antibiotics, primary bile acids and unconjugated sterols by the human breast cancer resistance protein (ABCG2). Biochem J. 2005 Jan 15;385(Pt 2):419-26.
• [9] Human organic anion transporters mediate the transport of tetracycline. Jpn J Pharmacol. 2002 Jan;88(1):69-76.
• [10] Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol. 2005 May;57(5):573-8.
• [11] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [12] Tetracycline affects abnormal properties of synthetic PrP peptides and PrP(Sc) in vitro. J Mol Biol. 2000 Jul 28;300(5):1309-22. doi: 10.1006/jmbi.2000.3840.
• [13] Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells. Food Chem Toxicol. 2017 Nov;109(Pt 1):253-263. doi: 10.1016/j.fct.2017.09.004. Epub 2017 Sep 4.
• [14] Synthesis and in vitro evaluation of targeted tetracycline derivatives: effects on inhibition of matrix metalloproteinases. Bioorg Med Chem. 2007 Mar 15;15(6):2368-74. doi: 10.1016/j.bmc.2007.01.026. Epub 2007 Jan 19.
• [15] Increased hepatic Fatty Acid uptake and esterification contribute to tetracycline-induced steatosis in mice. Toxicol Sci. 2015 Jun;145(2):273-82. doi: 10.1093/toxsci/kfv049. Epub 2015 Mar 4.
• [16] Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis. Toxicol Appl Pharmacol. 2016 Jul 1;302:1-9. doi: 10.1016/j.taap.2016.04.007. Epub 2016 Apr 16.
• [17] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.
• [18] 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.
• [19] Chlorzoxazone inhibits contraction of rat thoracic aorta. Eur J Pharmacol. 2006 Sep 18;545(2-3):161-6.
• [20] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [21] Inhibitory monoclonal antibodies to human cytochrome P450 1A2: analysis of phenacetin O-deethylation in human liver. Pharmacogenetics. 1998 Oct;8(5):375-82.
• [22] 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.
• [23] Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041-7.
• [24] 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.
• [25] 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.