Details of the Drug Combination

General Information of Drug Combination (ID: DCBP0V8)

• Drug Combination Name: Doxycycline + Terbinafine
• Indication: Ulcerative Colitis; Status: Phase 2 [1]
• Component Drugs:
  Doxycycline (DM7ICNU): Small molecular drug
  Terbinafine (DMI6HUW): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Doxycycline

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Actinomycosis	N.A.	Approved	[2]
Acute gonococcal cervicitis	N.A.	Approved	[2]
Acute gonococcal epididymo-orchitis	N.A.	Approved	[2]
Advanced gum disease	DA0D	Approved	[3]
Anthrax	1B97	Approved	[2]
Bartonellosis	N.A.	Approved	[2]
Boutonneuse fever	N.A.	Approved	[2]
Brill-Zinsser disease	N.A.	Approved	[2]
Bronchitis	CA20	Approved	[2]
Brucellosis	N.A.	Approved	[2]
Chancroid	N.A.	Approved	[2]
Chlamydiaceae infections	N.A.	Approved	[2]
Chronic periodontitis	DA0C.Y	Approved	[3]
Colorectal carcinoma	N.A.	Approved	[2]
Cutaneous anthrax	N.A.	Approved	[2]
Endemic typhus	N.A.	Approved	[2]
Epidemic louse-borne typhus	N.A.	Approved	[2]
Gastrointestinal anthrax	N.A.	Approved	[2]
Inhalational anthrax	N.A.	Approved	[2]
Listeriosis	N.A.	Approved	[2]
Lymphogranuloma venereum	N.A.	Approved	[2]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Ornithosis	N.A.	Approved	[2]
Q fever	N.A.	Approved	[2]
Relapsing fever	N.A.	Approved	[2]
Rickettsialpox	N.A.	Approved	[2]
Rickettsiosis	N.A.	Approved	[2]
Rocky mountain spotted fever	N.A.	Approved	[2]
Syphilis	N.A.	Approved	[2]
Trachoma	N.A.	Approved	[2]
Tularemia	1B94	Approved	[2]
Typhus	N.A.	Approved	[2]
Yaws	N.A.	Approved	[2]
Diabetic foot ulcer	BD54	Phase 2	[4]
Sinusitis	CA0A.Z	Investigative	[2]
Vibrio cholerae infection	1A00	Investigative	[2]

Doxycycline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 30S ribosomal RNA (Bact 30S rRNA)	TTOVFH2	NOUNIPROTAC	Modulator	[9]

Doxycycline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Doxycycline Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]

Doxycycline Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[12]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[8]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Expression	[8]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[13]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Activity	[14]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Decreases Activity	[14]
Neutrophil collagenase (MMP8)	OTZXH19L	MMP8_HUMAN	Decreases Activity	[14]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[15]
TAR DNA-binding protein 43 (TARDBP)	OTVOSFWW	TADBP_HUMAN	Decreases Expression	[16]

Indication(s) of Terbinafine

Disease Entry	ICD 11	Status	REF
Fungal infection	1F29-1F2F	Approved	[5]
Tinea corporis	1F28.Y	Approved	[6]
Tinea cruris	1F28.3	Approved	[6]
Tinea versicolor	1F2D.0	Approved	[6]
Onychomycosis	EE12.1	Phase 2	[7]
Tinea pedis	1F28.2	Investigative	[6]

Terbinafine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Squalene epoxidase (Candi ERG1)	TTM9XSU	ERG1_CANAL	Modulator	[9]

Terbinafine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[18]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[17]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[17]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[18]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[17]

Terbinafine Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[19]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[20]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[21]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[22]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[23]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[23]
Rho-related GTP-binding protein RhoC (RHOC)	OTOLE1FT	RHOC_HUMAN	Increases Localization	[24]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[24]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[21]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[24]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[21]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[21]
Paxillin (PXN)	OTVMMUOF	PAXI_HUMAN	Decreases Phosphorylation	[24]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Increases Localization	[24]
Rho-related GTP-binding protein RhoB (RHOB)	OTHQFQF7	RHOB_HUMAN	Decreases Expression	[24]
Focal adhesion kinase 1 (PTK2)	OT3Q1JDY	FAK1_HUMAN	Decreases Phosphorylation	[24]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[25]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[22]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Affects Response To Substance	[26]
Prostaglandin E2 receptor EP2 subtype (PTGER2)	OT1AUZAA	PE2R2_HUMAN	Increases Response To Substance	[27]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Response To Substance	[28]
Prostaglandin E2 receptor EP3 subtype (PTGER3)	OTQODQUN	PE2R3_HUMAN	Increases Response To Substance	[27]

References

• [1] ClinicalTrials.gov (NCT02606032) Trial of Antimicrobials Versus Placebo in Addition to Fecal Transplant Therapy in Ulcerative Colitis
• [2] Doxycycline 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: 6464).
• [4] ClinicalTrials.gov (NCT00764361) Safety Study of Topical Doxycycline Gel for Adult Diabetic Lower Extremity Ulcers. U.S. National Institutes of Health.
• [5] Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality. Ther Clin Risk Manag. 2005 Dec;1(4):299-306.
• [6] Terbinafine FDA Label
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):293-301.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [10] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [11] A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):272-8.
• [12] Functional and histochemical analysis of MDR3 P-glycoprotein in a tetracycline-controlled gene expression system. Eur J Med Res. 2000 Dec 29;5(12):517-22.
• [13] 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.
• [14] Synthesis and in vitro evaluation of targeted tetracycline derivatives: effects on inhibition of matrix metalloproteinases. Bioorg Med Chem. 2007 Mar 15;15(6):2368-74. doi: 10.1016/j.bmc.2007.01.026. Epub 2007 Jan 19.
• [15] Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion. Toxicol Sci. 2010 Jul;116(1):140-50. doi: 10.1093/toxsci/kfq085. Epub 2010 Mar 25.
• [16] A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. J Biomol Screen. 2014 Jan;19(1):44-56. doi: 10.1177/1087057113501553. Epub 2013 Sep 9.
• [17] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [18] Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab Dispos. 1999 Sep;27(9):1029-38.
• [19] Development of a strategy to identify and evaluate direct and indirect activators of constitutive androstane receptor in rats. Food Chem Toxicol. 2022 Dec;170:113510. doi: 10.1016/j.fct.2022.113510. Epub 2022 Nov 8.
• [20] A metoprolol-terbinafine combination induced bradycardia. Eur J Drug Metab Pharmacokinet. 2015 Sep;40(3):295-9.
• [21] Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway. Life Sci. 2010 Oct 23;87(17-18):537-44. doi: 10.1016/j.lfs.2010.08.010. Epub 2010 Sep 9.
• [22] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [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] Terbinafine inhibits endothelial cell migration through suppression of the Rho-mediated pathway. Mol Cancer Ther. 2006 Dec;5(12):3130-8. doi: 10.1158/1535-7163.MCT-06-0457.
• [25] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [26] Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos. 2011 Aug;39(8):1388-95. doi: 10.1124/dmd.110.037077. Epub 2011 May 3.
• [27] Suppressive effects of antimycotics on tumor necrosis factor-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Biochem Pharmacol. 2006 Aug 14;72(4):463-73. doi: 10.1016/j.bcp.2006.05.001. Epub 2006 Jun 19.
• [28] Association of Liver Injury From Specific Drugs, or Groups of?Drugs, With Polymorphisms in HLA and Other Genes in a?Genome-Wide Association Study. Gastroenterology. 2017 Apr;152(5):1078-1089. doi: 10.1053/j.gastro.2016.12.016. Epub 2016 Dec 30.