Details of the Drug Combination

General Information of Drug Combination (ID: DCRO0BE)

• Drug Combination Name: Isavuconazole + Dextromethorphan
• Indication: Pharmacokinetics of Isavuconazole; Status: Phase 1 [1]
• Component Drugs:
  Isavuconazole (DMSV12M): Small molecular drug
  Dextromethorphan (DMUDJZM): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Isavuconazole

Disease Entry	ICD 11	Status	REF
Candidemia	1F23.3Y	Phase 3	[2]
Invasive aspergillosis	1F20.0	Phase 3	[2]
Invasive candidiasis	1F23	Phase 3	[2]

Isavuconazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[5]

Indication(s) of Dextromethorphan

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[3]
Common cold	CA00	Approved	[3]
Cough	MD12	Approved	[4]
Fever	MG26	Approved	[3]
Headache	8A80-8A84	Approved	[3]
Rhinitis	FA20	Approved	[3]
Vasomotor/allergic rhinitis	CA08	Approved	[3]

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]

References

• [1] ClinicalTrials.gov (NCT01651325) Drug Interaction Study of Multiple Doses of Isavuconazole and Single Dose of Dextromethorphan in Healthy Adult Subjects
• [2] ClinicalTrials.gov (NCT00634049) Isavuconazole in the Treatment of Renally Impaired Aspergillosis and Rare Fungi. U.S. National Institutes of Health.
• [3] Dextromethorphan FDA Label
• [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: 6953).
• [5] Pharmacokinetic evaluation of CYP3A4-mediated drug-drug interactions of isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin Pharmacol Drug Dev. 2017 Jan;6(1):44-53.
• [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.