Details of the Drug Combination

General Information of Drug Combination (ID: DC1Z9XG)

• Drug Combination Name: Dextromethorphan + Diazoxide
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Dextromethorphan (DMUDJZM): Small molecular drug
  Diazoxide (DML1538): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 4.07
  Bliss Independence Score: 4.07
  Loewe Additivity Score: 4.69
  LHighest Single Agent (HSA) Score: 4.69

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dextromethorphan

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[2]
Common cold	CA00	Approved	[2]
Cough	MD12	Approved	[3]
Fever	MG26	Approved	[2]
Headache	8A80-8A84	Approved	[2]
Rhinitis	FA20	Approved	[2]
Vasomotor/allergic rhinitis	CA08	Approved	[2]

Dextromethorphan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor sigma 1 (OPRS1)	TT5TPI6	SGMR1_HUMAN	Agonist	[7]

Dextromethorphan Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[11]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[12]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[13]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[12]
Cholesterol 24-hydroxylase (CYP46A1)	DEKP5HX	CP46A_HUMAN	Metabolism	[14]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[15]
Cytochrome P450 130A1 (cyp130)	DE6CQ0I	CP130_MYCTU	Metabolism	[16]

Dextromethorphan Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Methylation	[17]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Methylation	[17]
Cholesterol 24-hydroxylase (CYP46A1)	OTJ27FOX	CP46A_HUMAN	Decreases Methylation	[14]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Response To Substance	[18]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Secretion	[19]
Beta-hexosaminidase subunit beta (HEXB)	OTROYLCR	HEXB_HUMAN	Increases Secretion	[19]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[19]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[19]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[20]
Mas-related G-protein coupled receptor member X2 (MRGPRX2)	OT2XA799	MRGX2_HUMAN	Affects Binding	[19]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Affects Metabolism	[6]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Affects Metabolism	[6]

Indication(s) of Diazoxide

Disease Entry	ICD 11	Status	REF
Congenital hyperinsulinism	5A4Y	Approved	[4]
Hyperinsulinemia	5A4Y	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Hypertensive emergency	BA03	Approved	[4]
Insulinoma	2C10.1	Approved	[4]
Malignant essential hypertension	BA00	Approved	[4]

Diazoxide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Modulator	[21]

Diazoxide Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[22]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[22]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Activity	[23]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[22]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[24]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[24]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[23]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Expression	[25]

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] Dextromethorphan FDA Label
• [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: 6953).
• [4] Diazoxide FDA Label
• [5] 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: 2409).
• [6] Comparison of various urine collection intervals for caffeine and dextromethorphan phenotyping in children. J Clin Pharmacol. 2004 Jul;44(7):708-14. doi: 10.1177/0091270004266624.
• [7] Dextromethorphan/quinidine: AVP 923, dextromethorphan/cytochrome P450-2D6 inhibitor, quinidine/dextromethorphan. Drugs R D. 2005;6(3):174-7.
• [8] Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities? Drug Metab Dispos. 2001 Nov;29(11):1514-20.
• [9] Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723.
• [10] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [11] Characterization of dextromethorphan N-demethylation by human liver microsomes. Contribution of the cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol. 1994 Jul 5;48(1):173-82.
• [12] Multiple human cytochromes contribute to biotransformation of dextromethorphan in-vitro: role of CYP2C9, CYP2C19, CYP2D6, and CYP3A. J Pharm Pharmacol. 1998 Sep;50(9):997-1004.
• [13] Enzymes in addition to CYP3A4 and 3A5 mediate N-demethylation of dextromethorphan in human liver microsomes. Biopharm Drug Dispos. 1999 Oct;20(7):341-6.
• [14] Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003 Dec 9;42(48):14284-92.
• [15] The bacterial P450 BM3: a prototype for a biocatalyst with human P450 activities. Trends Biotechnol. 2007 Jul;25(7):289-98.
• [16] Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets? Appl Microbiol Biotechnol. 2019 May;103(9):3597-3614.
• [17] Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos. 2004 Dec;32(12):1434-45. doi: 10.1124/dmd.104.001313. Epub 2004 Sep 21.
• [18] Myoclonus after dextromethorphan administration in peritoneal dialysis. Ann Pharmacother. 2011 Jan;45(1):e1. doi: 10.1345/aph.1P301. Epub 2010 Dec 14.
• [19] Dextromethorphan - A widely-used cough suppressant - Induces local anaphylaxis via MRGPRX2 on mast cells. Chem Biol Interact. 2020 Oct 1;330:109248. doi: 10.1016/j.cbi.2020.109248. Epub 2020 Aug 29.
• [20] Effects of common antitussive drugs on the hERG potassium channel current. J Cardiovasc Pharmacol. 2008 Dec;52(6):494-9. doi: 10.1097/FJC.0b013e31818eec8d.
• [21] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [22] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
• [23] Diazoxide-mediated preconditioning against apoptosis involves activation of cAMP-response element-binding protein (CREB) and NFkappaB. J Biol Chem. 2004 Nov 5;279(45):46748-54. doi: 10.1074/jbc.M406217200. Epub 2004 Aug 23.
• [24] Diazoxide-mediated growth inhibition in human lung cancer cells via downregulation of beta-catenin-mediated cyclin D1 transcription. Lung. 2009 Jan-Feb;187(1):61-7. doi: 10.1007/s00408-008-9127-1. Epub 2008 Dec 4.
• [25] Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):375-84. doi: 10.1016/j.taap.2012.11.015. Epub 2012 Nov 28.