Details of the Drug Combination

General Information of Drug Combination (ID: DC0F50P)

• Drug Combination Name: Doxepin + Miconazole
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  Doxepin (DMPI98T): Small molecular drug
  Miconazole (DMPMYE8): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 0.281
  Bliss Independence Score: 2.227
  Loewe Additivity Score: 0.779
  LHighest Single Agent (HSA) Score: 4.405

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Doxepin

Disease Entry	ICD 11	Status	REF
Anxiety	N.A.	Approved	[2]
Bipolar depression	N.A.	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Insomnia	7A00-7A0Z	Approved	[2]
Pruritus	EC90	Investigative	[2]

Doxepin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Inhibitor	[6]

Doxepin Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]

Doxepin Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[10]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[11]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[12]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[12]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Increases Expression	[12]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[12]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[12]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Increases Expression	[12]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[12]
Transgelin (TAGLN)	OTAEZ0KP	TAGL_HUMAN	Decreases Expression	[12]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[12]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[12]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[13]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[13]

Indication(s) of Miconazole

Disease Entry	ICD 11	Status	REF
Cutaneous candidiasis	1F23.14	Approved	[4]
Fungal infection	1F29-1F2F	Approved	[5]
Mycoses	1F2Z	Approved	[4]
Onychomycosis	EE12.1	Approved	[4]
Tinea corporis	1F28.Y	Approved	[4]
Tinea cruris	1F28.3	Approved	[4]
Tinea versicolor	1F2D.0	Approved	[4]
Tinea pedis	1F28.2	Investigative	[4]

Miconazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Modulator	[14]

Miconazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]

Miconazole Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[16]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[17]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[18]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Decreases Expression	[19]
Tyrosine aminotransferase (TAT)	OT2CJ91O	ATTY_HUMAN	Decreases Expression	[19]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[19]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[20]
Adenylate cyclase type 9 (ADCY9)	OT1IZT5K	ADCY9_HUMAN	Increases Activity	[21]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[22]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[23]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[23]
Cathepsin D (CTSD)	OTQZ36F3	CATD_HUMAN	Increases Expression	[24]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[24]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[25]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[24]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[24]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[26]

References

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• [2] Doxepin FDA Label
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• [4] Miconazole 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: 2449).
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• [16] Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression. Drug Metab Dispos. 2008 Feb;36(2):339-48.
• [17] The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
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• [19] Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol. 2006 Jul;70(1):329-39.
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• [21] Direct stimulation of adenylyl cyclase 9 by the fungicide imidazole miconazole. Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):497-504. doi: 10.1007/s00210-018-01610-1. Epub 2019 Jan 3.
• [22] The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicology. 2019 Sep 1;425:152247. doi: 10.1016/j.tox.2019.152247. Epub 2019 Jul 19.
• [23] Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis. J Invest Dermatol. 2001 Dec;117(6):1635-46. doi: 10.1046/j.0022-202x.2001.01566.x.
• [24] Miconazole induces protective autophagy in bladder cancer cells. Environ Toxicol. 2021 Feb;36(2):185-193. doi: 10.1002/tox.23024. Epub 2020 Sep 27.
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