Details of the Drug Combination

General Information of Drug Combination (ID: DCVR90N)

• Drug Combination Name: Quinidine + Dextromethorphan
• Indication: Diabetic neuropathy; Status: Phase 1 [1]
• Component Drugs:
  Quinidine (DMLPICK): N.A.
  Dextromethorphan (DMUDJZM): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Quinidine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[4]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[5]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[6]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]

Quinidine Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[10]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[10]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[11]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[11]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Affects Binding	[12]
Tumor necrosis factor receptor superfamily member 8 (TNFRSF8)	OTJ8UM8O	TNR8_HUMAN	Decreases Expression	[13]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Affects Binding	[12]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Affects Binding	[12]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[14]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[16]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[17]
Misshapen-like kinase 1 (MINK1)	OTKB0RA8	MINK1_HUMAN	Increases ADR	[17]
Potassium voltage-gated channel subfamily E member 1 (KCNE1)	OTZNQUW9	KCNE1_HUMAN	Increases ADR	[17]

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	[1]

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	[19]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[20]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[21]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[22]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[23]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[24]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[23]
Cholesterol 24-hydroxylase (CYP46A1)	DEKP5HX	CP46A_HUMAN	Metabolism	[25]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[26]
Cytochrome P450 130A1 (cyp130)	DE6CQ0I	CP130_MYCTU	Metabolism	[27]

Dextromethorphan Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[28]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[28]
Mas-related G-protein coupled receptor member X2 (MRGPRX2)	OT2XA799	MRGX2_HUMAN	Affects Binding	[28]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Affects Metabolism	[18]

References

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• [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] 10th North American ISSX meeting. October 24-28, 2000. Indianapolis, Indiana, USA. Abstracts. Drug Metab Rev. 2000;32 Suppl 2:137-340.
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• [6] In vitro metabolism of quinidine: the (3S)-3-hydroxylation of quinidine is a specific marker reaction for cytochrome P-4503A4 activity in human liver microsomes. J Pharmacol Exp Ther. 1999 Apr;289(1):31-7.
• [7] Drug Interactions Flockhart Table
• [8] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
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• [11] In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol Sci. 2007 Sep;99(1):162-73.
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• [13] HL60 cells halted in G1 or S phase differentiate normally. Exp Cell Res. 2002 Nov 15;281(1):28-38. doi: 10.1006/excr.2002.5654.
• [14] Control of mammary tumor cell growth in vitro by novel cell differentiation and apoptosis agents. Breast Cancer Res Treat. 2002 Sep;75(2):107-17. doi: 10.1023/a:1019698807564.
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• [16] Transport inhibition of digoxin using several common P-gp expressing cell lines is not necessarily reporting only on inhibitor binding to P-gp. PLoS One. 2013 Aug 16;8(8):e69394. doi: 10.1371/journal.pone.0069394. eCollection 2013.
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• [18] 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.
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• [20] Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723.
• [21] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003 Dec 9;42(48):14284-92.
• [26] The bacterial P450 BM3: a prototype for a biocatalyst with human P450 activities. Trends Biotechnol. 2007 Jul;25(7):289-98.
• [27] 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.
• [28] 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.