Details of the Drug Combination

General Information of Drug Combination (ID: DC8C7WP)

• Drug Combination Name: Doxepin + Pyrimethamine
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Doxepin (DMPI98T): Small molecular drug
  Pyrimethamine (DM5X7VY): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 17.401
  Bliss Independence Score: 21.13
  Loewe Additivity Score: 1.068
  LHighest Single Agent (HSA) Score: 1.586

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	[5]

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	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[6]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[8]

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	[9]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[10]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[11]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[11]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Increases Expression	[11]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[11]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[11]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Increases Expression	[11]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[11]
Transgelin (TAGLN)	OTAEZ0KP	TAGL_HUMAN	Decreases Expression	[11]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[11]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[11]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[12]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[12]

Indication(s) of Pyrimethamine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]

Pyrimethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Folate receptor alpha (FOLR1)	TTVC37M	FOLR1_HUMAN	Modulator	[13]

Pyrimethamine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[15]

Pyrimethamine Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[16]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[17]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[18]
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Decreases Expression	[19]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[20]
Beta-hexosaminidase subunit beta (HEXB)	OTROYLCR	HEXB_HUMAN	Affects Binding	[21]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Activity	[22]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[23]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[24]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[25]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[25]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[22]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[22]
Multidrug and toxin extrusion protein 2 (SLC47A2)	OTF2CNRD	S47A2_HUMAN	Decreases Activity	[16]
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Decreases Activity	[26]

References

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• [2] Doxepin FDA Label
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• [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: 4800).
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• [14] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [15] Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity. Drug Metab Dispos. 2018 May;46(5):592-599.
• [16] Interactions between Oroxylin A with the solute carrier transporters and ATP-binding cassette transporters: Drug transporters profile for this flavonoid. Chem Biol Interact. 2020 Jun 1;324:109097. doi: 10.1016/j.cbi.2020.109097. Epub 2020 Apr 16.
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• [19] The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase. J Biol Chem. 2022 Feb;298(2):101531. doi: 10.1016/j.jbc.2021.101531. Epub 2021 Dec 23.
• [20] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [21] Crystal structure of -hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone. J Med Chem. 2011 Mar 10;54(5):1421-9. doi: 10.1021/jm101443u. Epub 2011 Jan 25.
• [22] Pyrimethamine induces apoptosis of melanoma cells via a caspase and cathepsin double-edged mechanism. Cancer Res. 2008 Jul 1;68(13):5291-300. doi: 10.1158/0008-5472.CAN-08-0222.
• [23] Antifolate activity of pyrimethamine enhances temozolomide-induced cytotoxicity in melanoma cells. Mol Cancer Res. 2009 May;7(5):703-12. doi: 10.1158/1541-7786.MCR-08-0263. Epub 2009 May 12.
• [24] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [25] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [26] The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs. Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G248-54. doi: 10.1152/ajpgi.00224.2009. Epub 2009 Sep 17.